Spinal Muscular Atrophy Research News

Biogen Idec and Isis Pharmaceuticals Announce Global Collaboration for Antisense Program Targeting Spinal Muscular Atrophy

2012-01-04T08:58:00.002-06:00

Biogen Idec and Isis Pharmaceuticals Announce Global Collaboration for Antisense Program Targeting Spinal Muscular Atrophy

-- Biogen Idec has Option to Develop and Commercialize Promising Compound for Most Common Genetic Cause of Infant Mortality --

WESTON, Mass. & CARLSBAD, Calif., Jan 04, 2012 (BUSINESS WIRE) -- -- Biogen Idec's Expertise in Neurology to Aid in Rapid Development of ISIS-SMNRx --

Biogen Idec BIIB -0.03% and Isis Pharmaceuticals, Inc. ISIS -0.69% today announced that they have entered into an exclusive, worldwide option and collaboration agreement under which the companies will develop and commercialize Isis' antisense investigational drug, ISIS-SMNRx, for the treatment of spinal muscular atrophy (SMA).

SMA is a genetic neuromuscular disease characterized by muscle atrophy and weakness, and it is the most common genetic cause of infant mortality. One child out of every 10,000 births worldwide is born with SMA. Children with SMA generally appear normal at birth, with symptoms developing as early as a few months after birth, and in the most severe form of the disease, children have a significantly shortened lifespan. Isis' ISIS-SMNRx is designed to compensate for the underlying genetic defect that causes SMA.

Under the terms of the agreement, Isis will receive an upfront payment of $29 million and is eligible to receive up to $45 million in milestone payments associated with the clinical development of ISIS-SMNRx prior to licensing. Biogen Idec has the option to license ISIS-SMNRx until completion of the first successful Phase 2/3 trial. Isis could receive up to another $225 million in a license fee and regulatory milestone payments. In addition, Isis will receive double-digit royalties on sales of ISIS-SMNRx. Isis will be responsible for global development of ISIS-SMNRx through the completion of Phase 2/3 registrational clinical trials, with Biogen Idec providing advice on the clinical trial design and regulatory strategy. If Biogen Idec exercises its option, it will assume global development, regulatory and commercialization responsibilities.

"SMA is a heartbreaking disease -- it can kill children before their 2nd birthday and there are currently no therapies to treat the disease," said George A. Scangos, Ph.D., CEO of Biogen Idec. "It is exactly the kind of disease and program that we are focused on at Biogen Idec. The unmet need could not be any greater, the program fits with our mission to bring innovative therapies to patients with serious neurologic diseases, and Isis' antisense compound has the potential to be a highly effective, first-to-market therapy for this deadly disease. We have the utmost respect for Isis' scientific leadership and expertise in antisense technology, and we have crafted a collaboration that brings together our two companies' strengths toward a common goal."

"Biogen Idec's expertise in the global development and commercialization of innovative new therapies for neurologic diseases is a great strategic fit to advance ISIS-SMNRx," said Stanley T. Crooke, M.D., Ph.D., Chairman of the Board and Chief Executive Officer. "This alliance is consistent with our business strategy to develop antisense drugs to proof-of-concept with a knowledgeable partner that is committed to supporting the rapid development of the drug. Given the severity of the unmet need in SMA, our proof-of-concept studies should also serve as the registrational trials for ISIS-SMNRx. We believe that, together with Biogen Idec, we will be able to expeditiously develop this investigational drug in hopes of bringing to market an effective and desperately needed treatment to improve the lives of children with SMA."

About SMA

SMA is a severe genetic disease that affects approximately 30,000-35,000 patients in the United States, Europe and Japan. One in 50 people, the equivalent of about 6 million people in the United States, are carriers of the SMA gene. Carriers experience no symptoms and do not develop the disease. However, when both parents are carriers, there is a one in four chance that their child will have SMA. SMA is caused by a loss of, or defect in, the survival motor neuron 1 (SMN1) gene leading to a decrease in the survival motor neuron (SMN) protein. SMN is critical to the health and survival of nerve cells in the spinal cord responsible for neuromuscular growth and function. The severity of SMA correlates with the amount of SMN protein. Infants with Type 1 SMA, the most severe form of the disease, produce very little SMN protein and have a life expectancy of less than two years. Children with Type II have greater amounts of SMN protein but still have a shortened lifespan and are never able to stand independently. Children with Type III have a normal lifespan but accumulate life-long physical disabilities as they grow.

About ISIS-SMNRx

ISIS-SMNRx is designed to treat all types of childhood SMA by altering the splicing of a closely related gene (SMN2) to increase production of fully functional SMN protein. The United States Food and Drug Administration granted orphan drug status and fast track designation to ISIS-SMNRx for the treatment of patients with SMA. In December 2011, Isis initiated the first Phase 1 clinical study evaluating ISIS-SMNRx in children with SMA. The Phase 1 study is a single-dose, dose-escalation study designed to assess the safety, tolerability and the pharmacokinetic profile of the drug in children between the ages of 2 and 14 who are medically stable. In this study, ISIS-SMNRx will be administered intrathecally as a single injection directly into the spinal fluid. Isis plans to follow this study with a Phase 1 multiple-ascending dose study.

Isis acknowledges support from the following organizations for ISIS-SMNRx: Muscular Dystrophy Association, SMA Foundation, Families of SMA and intellectual property licensed from Cold Spring Harbor Laboratory and the University of Massachusetts Medical School.

About Biogen Idec

Through cutting-edge science and medicine, Biogen Idec discovers, develops and delivers to patients worldwide innovative therapies for the treatment of neurodegenerative diseases, hemophilia and autoimmune disorders. Founded in 1978, Biogen Idec is the world's oldest independent biotechnology company. Patients worldwide benefit from its leading multiple sclerosis therapies, and the company generates nearly $5 billion in annual revenues. For product labeling, press releases and additional information about the company, please visit www.biogenidec.com .

About Isis Pharmaceuticals

Isis is exploiting its leadership position in antisense technology to discover and develop novel drugs for its product pipeline and for its partners. Isis' broad pipeline consists of 28 drugs to treat a wide variety of diseases with an emphasis on cardiovascular, metabolic and severe and rare/neurodegenerative diseases, and cancer. Isis' partner, Genzyme, plans to commercialize Isis' lead product, mipomersen, following regulatory approval, which is expected in 2012. Isis' patents provide strong and extensive protection for its drugs and technology. Additional information about Isis is available at www.isispharm.com .

Biogen Idec Safe Harbor Statement

This press release contains forward-looking statements, including statements about product development and commercialization. These forward-looking statements may be accompanied by such words as "anticipate," "believe," "estimate," "expect," "forecast," "intend," "may," "plan," "will" and other words and terms of similar meaning. You should not place undue reliance on these statements. Drug development and commercialization involve a high degree of risk. Factors which could cause actual results to differ materially from current expectations include the risk that adverse safety events may occur, regulatory authorities may require additional information or may fail to approve any potential new therapy, product reimbursement may be limited or unavailable, there may be problems with manufacturing processes, intellectual property rights may not be adequately protected, and the other risks and uncertainties that are described in the Risk Factors section of Biogen Idec Inc.'s most recent annual or quarterly report and in other reports Biogen Idec Inc. has filed with the SEC. These statements are based on current beliefs and expectations and speak only as of the date of this press release. Biogen Idec Inc. does not undertake any obligation to publicly update any forward-looking statements.

Isis Safe Harbor Statement

This press release includes forward-looking statements regarding Isis' strategic alliance with Biogen Idec, and the discovery, development, activity, therapeutic potential and safety of ISIS-SMNRx. Any statement describing Isis' goals, expectations, financial or other projections, intentions or beliefs, including the planned commercialization of mipomersen, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. Isis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis' programs are described in additional detail in Isis' annual report on Form 10-K for the year ended December 31, 2010 and its most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company.

Isis Pharmaceuticals(R) is a registered trademark of Isis Pharmaceuticals, Inc.

Photos/Multimedia Gallery Available: http://www.businesswire.com/cgi-bin/mmg.cgi?eid=50120160&lang=en

SOURCE: Biogen Idec

        
        MEDIA CONTACTS: 
        Biogen Idec 
        Naomi Aoki, 781-464-3260 
        Director, Public Affairs 
        or 
        Isis Pharmaceuticals 
        Amy Blackley, 760-603-2772 
        Assistant Director, Corporate Communications 
        or 
        INVESTOR CONTACTS: 
        Biogen Idec 
        Kia Khaleghpour, 781-464-2442 
        Associate Director, Investor Relations 
        or 
        Isis Pharmaceuticals 
        Kristina Lemonidis, 760-603-2490 
        Director, Investor Relations

http://www.marketwatch.com/story/biogen-idec-and-isis-pharmaceuticals-announce-global-collaboration-for-antisense-program-targeting-spinal-muscular-atrophy-2012-01-04

BioTime to Produce Stem Cells for Research in Muscle Disorders ALAMEDA, Calif., Jan 03, 2012 (BUSINESS WIRE) -- BioTime, Inc. BTX +4.13% today announced that it has elected to market progenitors of muscle stem cells bearing hereditary diseases. BioTime will produce the products from five human embryonic stem (hES) cell lines from Reproductive Genetics Institute (RGI) of Chicago, Illinois. The muscle cell lines will display the genes for Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, spinal muscular atrophy Type I, facioscapulohumeral muscular dystrophy 1A, and Becker muscular dystrophy. The cell lines will be marketed researchers seeking new treatment modalities for these diseases. "In the first quarter of this year, we will offer medical researchers normal muscle progenitor cell lines that we have already produced from BioTime's existing hES cell lines, and later in 2012 we plan to add to our product line the novel muscle progenitor cells produced from RGI cell lines bearing the five genetic muscle diseases," said Michael West, Ph.D., BioTime's CEO. "BioTime's business strategy includes generating near-term revenues in the emerging field of regenerative medicine by bringing some of the most advanced stem cell technologies to the market as research products." Background Human embryonic stem (hES) cell lines are cells typically derived from excess preimplantation embryos, produced in the course of in vitro fertilization (IVF) treatment, that were otherwise destined to be discarded. Because stem cells are derived at very early stages of development, they are undifferentiated and capable of becoming all the cell types of the human body. hES cells therefore have a potential role in the development of novel cell-based therapies for a host of degenerative diseases such as the hereditary diseases borne by the hES stem cell lines we will acquire from RGI. As hES cells open the door to the discovery of new classes of pharmaceuticals, they are expected to increase our understanding of human development. Many couples carrying genes for inherited diseases are at significant risk of parenting children with muscular dystrophy and other devastating diseases. RGI has produced hES cell lines carrying genes for some of these hereditary diseases, and BioTime will use these cell lines to produce progenitor cells that will be offered to medical researchers. BioTime will differentiate the RGI hES cell lines into purified muscle progenitors using its ACTCellerate(TM) technology that allows the isolation of novel embryonic progenitor cells, which are at an intermediate stage between embryonic stem cells and fully differentiated cells. The progenitor cells are relatively easy to manufacture on a large scale and in a highly purified state, which may make it advantageous to work with these cells as opposed to hES cells. The progenitor cell lines may possess the ability to become a wide array of products never before available to the medical community, as they have potential applications in research, drug discovery, and human regenerative stem cell therapy. About BioTime, Inc. BioTime, headquartered in Alameda, California, is a biotechnology company focused on regenerative medicine and blood plasma volume expanders. Its broad platform of stem cell technologies is developed through subsidiaries focused on specific fields of applications. BioTime develops and markets research products in the field of stem cells and regenerative medicine, including a wide array of proprietary ACTCellerate(TM) cell lines, culture media, and differentiation kits. BioTime's wholly owned subsidiary ES Cell International Pte. Ltd. has produced clinical-grade human embryonic stem cell lines that were derived following principles of Good Manufacturing Practice and currently offers them for use in research. BioTime's therapeutic product development strategy is pursued through subsidiaries that focus on specific organ systems and related diseases for which there is a high unmet medical need. BioTime's majority owned subsidiary Cell Cure Neurosciences, Ltd. is developing therapeutic products derived from stem cells for the treatment of retinal and neural degenerative diseases. Cell Cure's minority shareholder Teva Pharmaceutical Industries has an option to clinically develop and commercialize Cell Cure's OpRegen(TM) retinal cell product for use in the treatment of age-related macular degeneration. BioTime's subsidiary OrthoCyte Corporation is developing therapeutic applications of stem cells to treat orthopedic diseases and injuries. Another subsidiary, OncoCyte Corporation, focuses on the diagnostic and therapeutic applications of stem cell technology in cancer, including the diagnostic productPanC-Dx(TM) currently being developed for the detection of cancer in blood samples, therapeutic strategies using vascular progenitor cells engineered to destroy malignant tumors. ReCyte Therapeutics, Inc. is developing applications of BioTime's proprietary induced pluripotent stem cell technology to reverse the developmental aging of human cells to treat cardiovascular and blood cell diseases. BioTime's newest subsidiary, LifeMap Sciences, Inc., is developing an online database of the complex cell lineages arising from stem cells to guide basic research and to market BioTime's research products. In addition to its stem cell products, BioTime develops blood plasma volume expanders, blood replacement solutions for hypothermic (low-temperature) surgery, and technology for use in surgery, emergency trauma treatment and other applications. BioTime's lead product, Hextend(R), is a blood plasma volume expander manufactured and distributed in the U.S. by Hospira, Inc. and in South Korea by CJ CheilJedang Corp. under exclusive licensing agreements. Additional information about BioTime, ReCyte Therapeutics, Cell Cure, OrthoCyte, OncoCyte, BioTime Asia, LifeMap Sciences, and ESI can be found on the web at www.biotimeinc.com . Forward-Looking Statements Statements pertaining to future financial and/or operating results, future growth in research, technology, clinical development, and potential opportunities for BioTime and its subsidiaries, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as "will," "believes," "plans," "anticipates," "expects," "estimates") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the business of BioTime and its subsidiaries, particularly those mentioned in the cautionary statements found in BioTime's Securities and Exchange Commission filings. BioTime disclaims any intent or obligation to update these forward-looking statements. To receive ongoing BioTime corporate communications, please click on the following link to join our email alert list: http://www.b2i.us/irpass.asp?BzID=1152&to=ea&s=0 SOURCE: BioTime, Inc.

2012-01-03T10:39:00.003-06:00

BioTime to Produce Stem Cells for Research in Muscle Disorders

ALAMEDA, Calif., Jan 03, 2012 (BUSINESS WIRE) -- BioTime, Inc. BTX +4.13% today announced that it has elected to market progenitors of muscle stem cells bearing hereditary diseases. BioTime will produce the products from five human embryonic stem (hES) cell lines from Reproductive Genetics Institute (RGI) of Chicago, Illinois. The muscle cell lines will display the genes for Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, spinal muscular atrophy Type I, facioscapulohumeral muscular dystrophy 1A, and Becker muscular dystrophy. The cell lines will be marketed researchers seeking new treatment modalities for these diseases.

"In the first quarter of this year, we will offer medical researchers normal muscle progenitor cell lines that we have already produced from BioTime's existing hES cell lines, and later in 2012 we plan to add to our product line the novel muscle progenitor cells produced from RGI cell lines bearing the five genetic muscle diseases," said Michael West, Ph.D., BioTime's CEO. "BioTime's business strategy includes generating near-term revenues in the emerging field of regenerative medicine by bringing some of the most advanced stem cell technologies to the market as research products."

Background

Human embryonic stem (hES) cell lines are cells typically derived from excess preimplantation embryos, produced in the course of in vitro fertilization (IVF) treatment, that were otherwise destined to be discarded. Because stem cells are derived at very early stages of development, they are undifferentiated and capable of becoming all the cell types of the human body. hES cells therefore have a potential role in the development of novel cell-based therapies for a host of degenerative diseases such as the hereditary diseases borne by the hES stem cell lines we will acquire from RGI. As hES cells open the door to the discovery of new classes of pharmaceuticals, they are expected to increase our understanding of human development.

Many couples carrying genes for inherited diseases are at significant risk of parenting children with muscular dystrophy and other devastating diseases. RGI has produced hES cell lines carrying genes for some of these hereditary diseases, and BioTime will use these cell lines to produce progenitor cells that will be offered to medical researchers.

BioTime will differentiate the RGI hES cell lines into purified muscle progenitors using its ACTCellerate(TM) technology that allows the isolation of novel embryonic progenitor cells, which are at an intermediate stage between embryonic stem cells and fully differentiated cells. The progenitor cells are relatively easy to manufacture on a large scale and in a highly purified state, which may make it advantageous to work with these cells as opposed to hES cells. The progenitor cell lines may possess the ability to become a wide array of products never before available to the medical community, as they have potential applications in research, drug discovery, and human regenerative stem cell therapy.

About BioTime, Inc.

BioTime, headquartered in Alameda, California, is a biotechnology company focused on regenerative medicine and blood plasma volume expanders. Its broad platform of stem cell technologies is developed through subsidiaries focused on specific fields of applications. BioTime develops and markets research products in the field of stem cells and regenerative medicine, including a wide array of proprietary ACTCellerate(TM) cell lines, culture media, and differentiation kits. BioTime's wholly owned subsidiary ES Cell International Pte. Ltd. has produced clinical-grade human embryonic stem cell lines that were derived following principles of Good Manufacturing Practice and currently offers them for use in research. BioTime's therapeutic product development strategy is pursued through subsidiaries that focus on specific organ systems and related diseases for which there is a high unmet medical need. BioTime's majority owned subsidiary Cell Cure Neurosciences, Ltd. is developing therapeutic products derived from stem cells for the treatment of retinal and neural degenerative diseases. Cell Cure's minority shareholder Teva Pharmaceutical Industries has an option to clinically develop and commercialize Cell Cure's OpRegen(TM) retinal cell product for use in the treatment of age-related macular degeneration. BioTime's subsidiary OrthoCyte Corporation is developing therapeutic applications of stem cells to treat orthopedic diseases and injuries. Another subsidiary, OncoCyte Corporation, focuses on the diagnostic and therapeutic applications of stem cell technology in cancer, including the diagnostic productPanC-Dx(TM) currently being developed for the detection of cancer in blood samples, therapeutic strategies using vascular progenitor cells engineered to destroy malignant tumors. ReCyte Therapeutics, Inc. is developing applications of BioTime's proprietary induced pluripotent stem cell technology to reverse the developmental aging of human cells to treat cardiovascular and blood cell diseases. BioTime's newest subsidiary, LifeMap Sciences, Inc., is developing an online database of the complex cell lineages arising from stem cells to guide basic research and to market BioTime's research products. In addition to its stem cell products, BioTime develops blood plasma volume expanders, blood replacement solutions for hypothermic (low-temperature) surgery, and technology for use in surgery, emergency trauma treatment and other applications. BioTime's lead product, Hextend(R), is a blood plasma volume expander manufactured and distributed in the U.S. by Hospira, Inc. and in South Korea by CJ CheilJedang Corp. under exclusive licensing agreements. Additional information about BioTime, ReCyte Therapeutics, Cell Cure, OrthoCyte, OncoCyte, BioTime Asia, LifeMap Sciences, and ESI can be found on the web at www.biotimeinc.com .

Forward-Looking Statements

Statements pertaining to future financial and/or operating results, future growth in research, technology, clinical development, and potential opportunities for BioTime and its subsidiaries, along with other statements about the future expectations, beliefs, goals, plans, or prospects expressed by management constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to statements that contain words such as "will," "believes," "plans," "anticipates," "expects," "estimates") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in the development and/or commercialization of potential products, uncertainty in the results of clinical trials or regulatory approvals, need and ability to obtain future capital, and maintenance of intellectual property rights. Actual results may differ materially from the results anticipated in these forward-looking statements and as such should be evaluated together with the many uncertainties that affect the business of BioTime and its subsidiaries, particularly those mentioned in the cautionary statements found in BioTime's Securities and Exchange Commission filings. BioTime disclaims any intent or obligation to update these forward-looking statements.

To receive ongoing BioTime corporate communications, please click on the following link to join our email alert list: http://www.b2i.us/irpass.asp?BzID=1152&to=ea&s=0

SOURCE: BioTime, Inc.

http://www.marketwatch.com/story/biotime-to-produce-stem-cells-for-research-in-muscle-disorders-2012-01-03

Happy holidays!

2011-12-22T10:21:00.000-06:00

Happy holidays to all the readers and best wishes for the new year.

Looking forward to some ground breaking progress finding a treatment for SMA in 2012!

Single Administration of Antisense Oligomer Delivered to the CNS Rescues a Severe Mouse Model of Spinal Muscular Atrophy

2011-12-22T10:19:00.000-06:00

Single Administration of Antisense Oligomer Delivered to the CNS Rescues a Severe Mouse Model of Spinal Muscular Atrophy.

December 22, 2011.

The Burghes laboratory at Ohio State University publishes a paper in Human Molecular Genetics showing a single dose of an antisense oligomer (ASO) can greatly benefit survival, weight gain, and motor function in severe mouse model of SMA.

In this study, the authors delivered a bolus ICV injection of anti-sense oligonucleotide (ASO) of morpholino chemistry to alter SMN2 splicing and increase SMN levels. Treated SMA mice had improvement in weight gain, motor activity, and increased survival from 15 days to over 100 days. Delayed CNS delivery (P4) had an intermediate advantage, evidence that earlier CNS treatment yields more robust effects, while delayed peripheral delivery after blood-brain-barrier maturation had only modest increased survival. This suggests that CNS delivery of SMN is key to therapeutic benefit in this SMA mouse model.

The authors suggest that CNS increases of SMN alone will likely have a major impact on SMA, and the early introduction by intrathecal delivery of morpholino oligomers is a potential treatment for SMA patients.

Click here to read the paper abstract.

Click here to learn more about ASO approaches to SMA.

Arthur Burghes, Ph.D. is a long serving member on the FSMA Scientific Advisory Board.

http://www.fsma.org/LatestNews/index.cfm?ID=6581&TYPE=1150

ISIS INITIATES PHASE 1 CLINICAL STUDY OF ISIS-SMNRX IN PATIENTS WITH SPINAL MUSCULAR ATROPHY

2011-12-19T15:27:00.002-06:00

ISIS INITIATES PHASE 1 CLINICAL STUDY OF ISIS-SMN_RX IN PATIENTS WITH SPINAL MUSCULAR ATROPHY

CARLSBAD, Calif., December 19, 2011 – Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced today that it has initiated a Phase 1 study of ISIS-SMNRx in patients with spinal muscular atrophy (SMA). SMA is a severe motor-neuron disease that is the leading genetic cause of infant mortality. Isis is developing ISIS-SMNRx as a potential treatment for all Types of SMA.

“SMA is a devastating disease that leads to the loss of motor neurons resulting in muscle weakness and respiratory failure in children. The genetic cause of this disease is well understood, but there are currently no effective disease-modifying therapies. Currently, treatment of SMA is entirely symptomatic and focuses on preserving muscle strength and lung function by physical therapy and assisted ventilation. This supportive approach has improved the natural history of SMA by extending life expectancy, but muscle weakness and atrophy are not affected. A disease-modifying drug like ISIS-SMNRx that specifically targets the cause of the disease could, for the first time, restore muscle strength and respiratory function and dramatically improve the children’s function and quality of life,” said Darryl C. De Vivo, M.D, Sidney Carter Professor of Neurology and Pediatrics and Co-Director of the Motor Neuron Center at Columbia University Medical Center.

SMA is a severe genetic disease that affects approximately 30,000 – 35,000 patients in the United States, Europe and Japan. One in 50 people, approximately 6 million people in the United States, are carriers of the SMA gene. Carriers experience no symptoms and do not develop the disease, however, when both parents are carriers, there is a one in four chance that their child will have SMA. SMA is caused by a loss of, or defect in, the survival motor neuron 1 (SMN1) gene leading to a decrease in the protein, survival motor neuron (SMN). SMN is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular growth and function. The severity of SMA correlates with the amount of SMN protein. Infants with Type 1 SMA, the most severe life-threatening form, produce very little SMN protein and have shortened life expectancy. Children with Type II and Type III have greater amounts of SMN protein and less severe, but still life-altering forms of SMA. ISIS-SMNRx is designed to treat all types of childhood SMA by altering the splicing of a closely related gene (SMN2) that leads to the increased production of fully functional SMN protein.

“Our strategy to treat SMA relies on a simple, powerful antisense method that boosts SMN protein levels by fixing a genetic RNA splicing glitch. Working with Isis, we have successfully redirected splicing to increase functional SMN production. We have thoroughly validated this approach in multiple animal models, observing marked improvement in modifying the disease course in both mild and severe models of SMA,” said Adrian Krainer, Ph.D., Professor of Molecular Genetics at Cold Spring Harbor Laboratory in Long Island, NY. “We look forward to translating this important discovery into an effective treatment for this serious disease.”

“SMA represents a serious unmet medical need with no currently available treatments. ISIS-SMNRx is our first drug to intervene in the splicing of RNA to increase the production of a normal protein, SMN. Together with Dr. Krainer’s lab, we have validated the antisense approach to treating this disease and are now advancing this program into clinical studies,” said C. Frank Bennett, Ph.D., Senior Vice President of Research at Isis. “We are committed to quickly developing this drug and are finalizing what we believe will be a rapid development path for this drug in all types of SMA. Once we evaluate ISIS-SMNRx as a single-dose in children with SMA, we will move to multiple-doses in our Phase 1 studies and eventually evaluate the drug in Phase 2 studies in children with SMA, including infants with Type I SMA.”

The Phase 1 study of ISIS-SMNRx is a single-dose, dose-escalation study designed to assess the safety, tolerability and pharmacokinetic profile of the drug in children with SMA between the ages of 2-14 who are medically stable. In this study, ISIS-SMNRx will be administered intrathecally as a single injection directly into the spinal fluid. Intrathecal administration of an antisense drug, ISIS-SOD1Rx, has been shown to be safe and well tolerated in an ongoing Phase 1 study in patients with amyotrophic lateral sclerosis.

“SMA is a heartbreaking disease. Children with SMA are bright and engaging, but often never achieve the simplest motor milestones like walking, crawling, and sitting up. Many do not live to reach kindergarten. In milder cases, SMA patients inexorably grow weaker and experience the loss of the few abilities they did acquire. In addition to motor losses, SMA patients young and old are at constant risk of tragic consequences from simple respiratory infections that you and I take in stride,” said Karen S. Chen, Ph.D., Chief Scientific Officer at the SMA Foundation. “If you consider that this is the normally bleak clinical outlook for these patients, you can understand why the ISIS-SMNRx trial represents such a watershed moment for SMA. The landmark science behind ISIS-SMNRx is compelling and it has a chance to fill the therapeutic void for SMA and transform the hopes and futures of thousands of patients and families.”

“We are very pleased to see the great milestone of a disease-modifying drug treatment advancing into clinical trials in SMA patients,” said Kenneth Hobby, President of Families of SMA. “Our community has worked for a long time to reach the goal of moving specific therapies for SMA from the bench and into the clinic. This has been made possible by close interactions between basic researchers, families, clinicians, and industry. Families of SMA applauds ISIS for investing in and leading drug developments efforts for this devastating, orphan disease.”

“We see real promise in therapeutic strategies for SMA that increase production of the SMN protein,” said Muscular Dystrophy Association Executive Vice President Research and Medical Director Valerie Cwik, M.D. “We’re delighted ISIS Pharmaceuticals is moving forward with a Phase 1 dose-escalation study of its antisense drug in children with SMA.”

Isis acknowledges support from the following organizations for this program: Muscular Dystrophy Association, SMA Foundation, Families of SMA and intellectual property licensed from Cold Spring Harbor Laboratory and the University of Massachusetts Medical School.

The United States Food and Drug Administration granted Orphan Drug Designation with Fast Track Status to ISIS-SMNRx for the treatment of patients with SMA.

For more information on the Phase 1 study of ISIS-SMNRx please visit: www.clinicaltrials.gov.

About Splicing
Splicing is a normal mechanism that the cell uses in order to produce many different, but closely related proteins from a single gene by varying the processing of the RNA. It is estimated that of the approximately 25,000 genes in the human genome, approximately 90% have alternative splice forms. In some cases, alternative splicing of RNA results in the production of proteins that are involved in disease. These diseases are referred to as splicing diseases and include SMA, cystic fibrosis and Duchenne’s muscular dystrophy.

ABOUT COLD SPRING HARBOR LABORATORY
Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL’s multidisciplinary scientific community is more than 350 scientists strong and its Meetings & Courses program hosts more than 11,000 scientists from around the world each year. Tens of thousands more benefit from the research, reviews, and ideas published in journals and books distributed internationally by CSHL Press. The Laboratory’s education arm also includes a graduate school and programs for undergraduates as well as middle and high school students and teachers. CSHL is a private, not-for-profit institution on the north shore of Long Island. For more information, visit www.cshl.edu.

ABOUT THE UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL
The University of Massachusetts Medical School attracts more than $300 million in research funding annually, and its innovative programs are the centerpiece of the Massachusetts Life Sciences Initiative. Consistently ranked by U.S.News & World Report as one of the leading medical schools in the nation for primary care education, UMMS is a leader in health sciences education, research and public service and home to 2006 Nobel Laureate Craig C. Mello, PhD, co-discoverer of RNA interference. UMMS is the academic partner of UMass Memorial Health Care. To learn more, visit www.umassmed.edu.

ABOUT ISIS PHARMACEUTICALS, INC.
Isis is exploiting its leadership position in antisense technology to discover and develop novel drugs for its product pipeline and for its partners. Isis’ broad pipeline consists of 28 drugs to treat a wide variety of diseases with an emphasis on cardiovascular, metabolic and severe and rare/neurodegenerative diseases, and cancer. Isis’ partner, Genzyme, plans to commercialize Isis’ lead product, mipomersen, following regulatory approval, which is expected in 2012. Isis’ patents provide strong and extensive protection for its drugs and technology. Additional information about Isis is available at www.isispharm.com.

ISIS PHARMACEUTICALS’ FORWARD-LOOKING STATEMENT
This press release includes forward-looking statements regarding the discovery, development and potential of drugs for severe and rare diseases, and the development, activity, therapeutic potential and safety of ISIS-SMNRx. Any statement describing Isis’ goals, expectations, financial or other projections, intentions or beliefs, including the planned commercialization of mipomersen, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. Isis’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Isis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Isis. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Isis’ programs are described in additional detail in Isis’ annual report on Form 10-K for the year ended December 31, 2010 and its most recent quarterly report on Form 10-Q, which are on file with the SEC. Copies of these and other documents are available from the Company.

Roche Enters Race to Cure Genetic Disease With $490 Million Agreement

2011-11-29T08:51:00.001-06:00

Roche Enters Race to Cure Genetic Disease With $490 Million Agreement

By Robert Langreth - Nov 29, 2011 6:45 AM CT

Roche Holding AG (ROG) will pay as much as $490 million for experimental drugs from PTC Therapeutics Inc. to treat a genetic muscle-weakening disease, in a deal that sets up a race with rivalNovartis AG. (NOVN)

The Basel, Switzerland-based drugmaker will pay closely held PTC Therapeutics $30 million up front, and another $460 million if a drug for spinal muscular atrophy achieves certain regulatory and commercial goals, the companies said today in a statement. PTC, based in South Plainfield, New Jersey, would also get royalties on sales of drugs from the collaboration.

Spinal muscular atrophy afflicts 18,000 people in the U.S. and Europe and causes progressive muscle weakness, according to the Spinal Muscular Atrophy Foundation. Kids with severe cases die within a few years, while those with mild cases can live a normal lifespan with disabilities. There are no approved medicines to treat the causes of the rare disorder, said Luca Santarelli, senior vice president of neuroscience at Roche.

“There are absolutely no therapeutic options for these children,” said Santarelli in a phone interview. “It is a frightening disease.”

As part of the agreement announced today, the two companies will work with the SMA Foundation in New York to advance a drug for spinal muscular atrophy into human trials. The foundation also is collaborating with Novartis, based in Basel, Switzerland, on a separate program to develop drugs for SMA, also at the preclinical stage.

In a third effort, the foundation has funded a researcher at Cold Spring Harbor Laboratory whose work has led to an experimental drug for the disease at Isis Pharmaceuticals Inc. (ISIS) in Carlsbad, California. The therapy may enter human trials in December or January, an Isis spokesman said in an e-mail.

Hedge-Fund Founder

In an unusual arrangement, experts from the foundation will sit on a steering committee with scientists from Roche and PTC to help move the drugs into human trials. The foundation was created in 2003 by Dinakar Singh, who started and runs the hedge fund TPG-Axon Capital Management LP, to help find a cure for his sixth-grade daughter Arya and other patients with the disease.

Singh and his wife, Loren Eng, have spent almost $100 million of their money on research toward an SMA treatment, including $13 million in grants the foundation has given to PTC since 2006.

‘Breaking New Ground’

The three-way collaboration among Roche, PTC and the SMA Foundation “is certainly breaking new ground,” said Claudia Hirawat, senior vice president for corporate development at PTC, in a telephone interview. “I am not aware of any collaboration that follows exactly this structure.”

Children with the disease lack a gene called SMN1 that produces a protein crucial for the health of neurons that control muscles, said Santarelli. The PTC drugs activate a backup gene so it produces more of the needed protein, he said.

PTC has been working with Roche on other diseases since 2009. Early this year, PTC’s Hirawat told Roche about the progress the company been making on spinal muscular atrophy, leading to serious discussions about a potential collaboration starting in June, she said.

PTC’s experimental compounds “target the cause not the symptoms” of the genetic disease,’’ said Santarelli of Roche. “Not too many times do you get to do that.”

Santarelli said he was driving from Switzerland to Italy during a vacation last July when he got an urgent call from two of his colleagues who had seen data from PTC’s tests of its compounds in mice.

“They were super-excited,” he said. “They were saying, ‘You have to see this, you have to see this.’”

Mice Findings

The data showed that mice that normally die in two weeks were “living 10 times as long” after being treated with PTC’s drug, he said. It was compelling enough that he and Jean-Jacques Garaud, Roche’s head of pharma research and early development, flew in September to visit PTC, leading to the deal, Santarelli said.

Santarelli said that it may be two years before a drug from the collaboration could reach human trials if all goes well.

“If we are lucky,” the pace may be faster, he said, “but I don’t want to raise expectations. We are going into children so we have to be very sure that the drug is safe.”

Eng, president of the SMA Foundation, said her organization is working with numerous drug companies because multiple types of drugs acting on different mechanisms may be needed to treat the disease, in the same way that AIDS is treated with multidrug cocktails

“At the time your child is diagnosed with something like this and they tell you there is no treatment, your fantasy is that some big drug company is going to come and save the day,” Eng said in a phone interview. “It borders on a miracle given all the little diseases they could be working on, they are working on this.”

To contact the reporters responsible for this story: Robert Langreth in New York atrlangreth@bloomberg.net;

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

http://www.bloomberg.com/news/2011-11-29/roche-enters-race-to-cure-genetic-disease-with-490-million-agreement.html

Mouse study offers hope for treating leading genetic cause of infant death

2011-11-28T08:48:00.001-06:00

Mouse study offers hope for treating leading genetic cause of infant death

28 November 2011

By Suzanne Elvidge

Appeared in BioNews 635

Researchers have made a step forward in the treatment of spinal muscular atrophy, a serious genetic disorder, by using a stretch ofRNA to trigger mice into producing a back-up version of a missing protein.
Spinal muscular atrophy, a genetic disease causing progressive muscular weakness, particularly affects children. People with the disease are missing a gene, SMN-1, which codes for the protein SMN. This protein supports and maintains motor neurones, and without it, messages are not passed from nerves to muscles. There is a 'back-up' version of the gene, known as SMN-2, but this produces lower levels of SMN, along with partly-functioning versions of the protein, and the severity of spinal muscular atrophy depends on the number of copies of the back-up gene.
The researchers used a mouse model of spinal muscular atrophy that had been engineered to carry a partly functioning version of the gene SMN-2. The mice were given a synthetic stretch of RNA that triggered the back-up gene to make full copies of the SMN protein, and these mice lived longer, moved better and gained more weight.
This is a study using a mouse model of the disease, so the treatment of humans, even in clinical studies, is still a way off. The next step for the team is to carry out tests on transgenic pigs with spinal muscular atrophy, which have been newly developed for this project. If these are successful, however, this could lead to a treatment for a currently incurable and often fatal disease, and could open up research in other similar inherited disorders.
Chris Lorson, researcher at the Bond Life Sciences Center, professor in the Department of Veterinary Pathobiology and the Department of Molecular Microbiology and Immunology and co-author of the study, said: 'It's been remarkable to watch how quickly SMN-2 knowledge has transformed from basic molecular biology to being modified targets for novel therapeutics. SMN-2 is like a light that's been dimmed, and we're trying anything to get it brighter. Even turning it up a little bit would help dramatically'.
Spinal muscular atrophy is the leading genetic cause of infant death worldwide, and the second leading cause of neuromuscular disease, affecting one in 6000 people. It not always fatal during childhood, however, and patients with less severe forms of the disease may survive into adulthood and occasionally old age. Around one in 30 people carry a copy of the defective gene causing spinal muscular atrophy, and if two carriers have a child, each child has a one in four chance of having spinal muscular atrophy.

http://www.bionews.org.uk/page_113119.asp

Synthetic RNA Eases Fatal Disease

2011-11-23T10:16:00.001-06:00

Synthetic RNA Eases Fatal Disease

November 23, 2011
A team of Univ. of Missouri researchers have found that targeting a synthetic molecule to a specific gene could help the ease severity of the disease Spinal Muscular Atrophy (SMA)–the leading genetic cause of infantile death in the world.

“When we introduced synthetic RNA into mice that carry the genes responsible for SMA, the disease’s severity was significantly lowered,” says Chris Lorson, researcher at the Bond Life Sciences Center and professor in the Department of Veterinary Pathobiology and the Department of Molecular Microbiology and Immunology. “The mice that receive synthetic RNA gain more weight, live longer, and had improvements in motor skills. These results are very exciting.”

SMA is a rare genetic disease that is inherited by one in 6,000 children, who often die young because there is no cure. Children who inherit SMA are missing a gene that produces a protein which directs nerves in the spine to give commands to muscles. Lorson’s lab focuses on targeting a partially functioning back-up copy of the missing gene, known as SMN-2, into producing the needed protein.

While the results are promising, Lorson notes additional research is needed before synthetic RNA could be used on humans for SMA. Clinical trials for similar synthetic RNAs are currently being performed in other neurodegenerative disease such as Lou Gehrig’s or ALS. In SMA, there are clinical trials taking place in many labs across the country that are investigating drug compounds to increase SMN-2 protein production.

“It’s been remarkable to watch how quickly SMN-2 knowledge has transformed from basic molecular biology to being modified targets for novel therapeutics,” Lorson says. “SMN-2 is like a light that’s been dimmed, and we’re trying anything to get it brighter. Even turning it up a little bit would help dramatically.”

The study, “Bifunctional RNAs Targeting the Intronic Splicing Silencer N1 Increase SMN Levels and Reduce Disease Severity in an Animal Model of Spinal Muscular Atrophy,” was published in the journal Molecular Therapy. Co-authors include Erkan Osman and Pei-Fen Yen of the Univ. of Missouri.

Source: Univ. of Missouri
http://www.laboratoryequipment.com/news-Synthetic-RNA-Eases-Fatal-Disease-112311.aspx?xmlmenuid=51

Not completely related to SMA but an article about Stem Cells

2011-11-15T15:47:00.001-06:00

This Might Be the End of Embryonic Stem Cell Research

A biotech company that after much turmoil and huge expense launched the first human embryonic stem cell clinical trial in the United States is getting out of the stem cell business.

Geron led the charge to push the U.S. government and society at large to allow use of embryonic stem cells. Scientists believed they could treat myriad diseases because of their ability to become any cell in the human body. But the company has accumulated losses of almost $300 million over the past four years and has halted its stem cell efforts. With few scientists pursuing stem cell research of the embryonic variety, many are wondering if embryonic stem cell research will soon take its final breath.

The cells are controversial because human embryos are destroyed to obtain them. But the company persevered amidst years of public outcry and political punditry and in October 2011 launched the first-ever FDA-approved human trial to treat acute spinal cord injuries. Just four of the 10 approved patients have been treated with Geron's cells, and now it looks like the other six won't have their chance. A recently-launched Swiss trial run by Geron will also presumably be halted. The company has laid of 34 percent of its staff and will focus now on cancer treatments. Manypatients who held out hope for a paralysis cure will be sorely disappointed.

Advanced Cell Technology is one of the only companies (Stem Cells is another) still using embryonic stem cells. It has human clinical trials active in macular dystrophy and macular degeneration.

But other companies, like Neuralstem, are poised to pick up the slack using a different and less controversial type of stem cell. Neuralstem uses neural rather than embryonic stem cells, and has already seen remarkable success treating ALS (AKA Lou Gehrig's disease) patients, which I wrote about here. Neural stem cells are not completely free of controversy: they are taken from a voluntarily aborted fetus. But embryos are not destroyed in order to obtain them. And Neuralstem's technology allows them to proliferate all the cells they need from a single fetus.

"This was not a surprise to me," Richard Garr, CEO of Neuralstem, said about the Geron news. "I think the writing was on the wall when Tom Okarma was either pushed out or left on his own. It was pretty clear the they were not interested in being a stem cell company at that point."

Okarma was Gerons's CEO for 13 years and was the public face of the company's fight to use embryonic stem cells.

Meanwhile, Neuralstem has already treated 12 ALS patients, and doctors will treat number 13 on Friday. Garr believes his cells are easier to control and target than embryonic stem cells for treating neural diseases.

Next up for Neuralstem is a human trial testing their cells in chronic spinal cord patients. So we might be saying goodbye to Geron, but not to the hope of spinal cord injured folks getting out of their wheelchairs. [San Francisco Business Times]

http://gizmodo.com/5859768/this-might-be-the-end-of-embryonic-stem-cell-research

FOX MEDICAL TEAM: ALS Stem Cell Surgery

2011-11-14T12:18:00.001-06:00

Reposting a comment posted by Tom.

FOX MEDICAL TEAM: ALS Stem Cell Surgery

Updated: Wednesday, 09 Nov 2011, 8:46 PM EST
Published : Wednesday, 09 Nov 2011, 6:15 PM EST

Beth
Galvin

By MYFOXATLANTA STAFF/myfoxatlanta

ATLANTA - It's been almost 19 months since John Conley underwent a dangerous, first-of-its kind operation. Surgeons at Emory opened up his spinal cord and injected it with stem cells.

Conley is part of a study to determine whether the surgery and the cells are safe.

As Conley’s muscles grow weaker, his dog, Dalton, is taking over tasks, like helping John get dressed.

"To me he's a miracle, and what they do is just incredible, the dogs,” Conley said.

It's been a year, since John, diagnosed with the muscle-wasting disease ALS in 2009, underwent a risky, cutting-edge surgery at Emory University Hospital.

Neurosurgeon Dr. Nicholas Boulis and his team opened up John's spinal cord, and injected close to a half million fetal stem cells, reproduced in a lab from a fetus aborted twenty years ago.

Neurologist Dr. Jonathan Glass says this is only a safety trial, so John and other 11 ALS patients had no guarantees they'll see any benefit.

"The question is if you put them under anesthesia and put them through three or four hours of surgery, are they going to do okay? And remarkably, remarkably, they did very very well,” said Glass.

So well that the Food and Drug Administration has given the Emory team the go-ahead to take the next step.

Next Friday, Boulis will move the injection site or lower spinal cord, which controls our legs, up to the neck, which controls breathing.

“The reason people die from ALS is because they can't breathe,” said Glass. “So, if we can maintain respiratory function by supporting those muscles, by supporting the motor neurons that support those muscles, then I think we've done something that changes the course of the disease. That's actually kept people alive longer. That's really our goal at this point.”

"The risk is substantially higher going into the cervical spinal cord and yet, that's where we have to go, if we're going to do what we want to do for these patients,” said Boulis.

Nineteen months after his operation, John says he's doing okay.

"Mentally? Remarkable. Physically, it's interesting,” said Connelly.

His muscles have continued to grow weaker, but there are days John says he feels good -- even strong.

“I'm not saying it's the stem cells, it could be just the positive mental attitude, and the fact that you're not going to quit,” said Conley.

Since his surgery, John has become a grandfather, not once, but twice And the chance, he would have the operation - again.

“People have taught me a lot about the meaning of life, and it's tough. We lose them all for the most part, and we're hoping that that will change. And that's why we're doing what we're doing. John has become a good friend,” said Glass.

"My outlook is I live every day to the fullest. I don't think about the disease. We don't talk about it too much,” said Conley.

A week from Friday, Dr. Boulis will operate on one the first of six patients in this new stage of the trial. He'll open up the patient's cervical spinal cord, and inject the stem cells directly into the cord. The stakes are higher, but so is the potential benefit.

They are still looking for patients willing to be a part of this study.http://www.myfoxatlanta.com/dpp/health/FOX-MEDICAL-TEAM%3A-ALS-Stem-Cell-Surgery-20111109-pm-pk

Repligen Provides Update on the Phase I Trial for Families of Spinal Muscular Atrophy Drug RG3039.

2011-10-29T10:34:00.002-05:00

http://www.fsma.org/LatestNews/index.cfm?ID=6491&TYPE=1150

Vertex Success in CF Drug Development Leads Way for Other Orphan Diseases such as Spinal Muscular Atrophy: NDA filed.

2011-10-23T10:23:00.002-05:00

http://www.fsma.org/Research/News/index.cfm?ID=6477&TYPE=1158

USC Scientist Targets the No. 1 Genetic Cause of Infant Mortality

2011-10-13T10:34:00.000-05:00

http://www.healthcanal.com/genetics-birth-defects/21835-USC-Scientist-Targets-the-Genetic-Cause-Infant-Mortality.html

New Research Probes Spinal Muscular Atrophy, Guiding DrugCompanies to Develop Better Treatments

The disease is heartbreaking. It turns babies into ragdollsand extinguishes lives just as they are getting started. But one USC scientistis working to unravel the mystery behind the leading genetic cause of infantmortality, uncovering how Spinal Muscular Atrophy disconnects muscles from themind.

Spinal Muscular Atrophy, or SMA, is a neurodegenerativedisease caused by a recessive gene mutation that results in a deficiency of theSurvival of Motor Neuron, or SMN, protein. In a phenomenon called "denervation,"neurons lose their physical connection to muscles, resulting in a loss of motorcontrol and muscle weakness.

A team of researchers lead by Chien-Ping Ko of the USCDornsife College of Letters, Arts and Sciences has generated the firstextensive study of severe denervation occurring in specific muscles affected bySMA. The data allows them to measure the effectiveness of drug treatments, andwill act as a springboard for future research that explores the cause of SMA.

One in every 40 to 50 people carries the gene for SMA. Iftwo carriers have a child together, there is a 25 percent chance that the childwill be affected. As a result, one in every 6,000 to 10,000 babies is born withSMA.

While SMA has multiple types varying in symptom severity andlife expectancy, in its most severe type, SMA prevents babies from even beingable to sit up. The prognosis in these cases is not good – most die beforereaching two years of age.

"That's why you don't often hear of this disease,"said Ko, professor and head of neurobiology at Dornsife. "They die soyoung."

Ko and his team are working to pull back the shroud andunderstand SMA better by tracing neurons down to specific muscles in miceaffected by SMA to see exactly where the disease take its toll.

"We are interested in what happens at the neuromuscularjunction." Ko worked with USC graduate researchers Karen K. Y. Ling,Rebecca M. Gibbs, and Zhihua Feng. Their study was published online this monthby Human Molecular Genetics in advance of appearing in a print edition of thejournal.

The results were odd, but enlightening. Muscles along thespine and hindquarters down to the legs showed varying — not uniform — degreesof denervation. For example, several muscles controlling movement in the headand neck were severely affected, while other neighboring muscles were barelyaffected at all. Many of the affected muscles are involved in vital motorfunctions that are lost in patients, such as breathing, feeding, and posture.

"So far, we don't know the mechanism causing the lossof synapses in some muscles and not in others," Ko said. "But this isa good preparation to study that."

In addition, the knowledge of which muscles are affected andby how much is allowing pharmaceutical companies to quantitatively gauge theresults of drug trials.

For example, although trichostatin A (TSA) has long beenknown to fight the disease in SMA animal models, Ko was able to determineexactly how much it reversed denervation in each individual muscle.

Ko is showing drug companies how to replicate his techniqueso that they can develop more effective drugs.

"Maybe we will have a way to mitigate or prevent theloss," Ko said.

The research was funded by the National Institutes ofHealth, the Muscular Dystrophy Association, the Spinal Muscular AtrophyAssociation, and the Families of SMA.

Antisense Therapy Improves Lifespan and Motor Function in Mice with Severe Spinal Muscular Atrophy

2011-10-06T10:04:00.002-05:00

Scientists have used an antisense oligonucleotide (ASO) to significantly prolong the lifespan and improve motor function in mice with a severe form of the motor neuron disease spinal muscular atrophy (SMA). The approach involved administering an ASO that corrects SMN2 splicing and restores SMN protein expression in motor neurons and other tissues and organs, in particular the liver.

The Cold Spring Harbor Laboratory (CSHL) researchers found that injecting the ASO directly into the CNS of SMA mice efficiently corrected SMN2 splicing, raised SMN protein levels, and led to a modest increase in survival. However, report Adrian R. Krainer, Ph.D., and colleagues at CSHL and colleagues at Isis Pharmaceuticals, systemic treatment involving two subcutaneous injections of the antisense oligonucleotide boosted survival even further, while combining the two routes of administration increased survival 10-fold compared with CNS administration alone. The researchers report their findings in Nature. The paper is titled “Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model.”

SMA results from loss-of function mutations in the survival motor neuron 1 (SMN1) gene. Non-central nervous system pathologies, including cardiovascular defects, have also recently been reported in severe SMA mouse models and patients, the authors report. Humans do carry a paralogue gene, SMN2, but a splicing glitch means its exon 7 is predominantly missed out, and the limited amount of functional, full length SMN expressed can’t compensate for lack of SMN1.

The team set out to compare the effects of either intracerebroventricular (ICV) injection or systemic administration of an ASO called ASO-10-27, in a severe mouse model of SMA that is deficient in the SMN protein. ASO-10-27 had previously been shown to effectively correct SMN2 splicing and restore SMN expression in motor neurons after ICV injections.

For the latest set of studies SMA mice received either a single ICV injection of ASO-10-27 on postnatal day one (P1), or two separate subcutaneous (SC) injections between P0 and P3. The team in addition evaluated combined treatment regimens in which animals were given both ICV and SC injections, or repeated SC injections.

While ICV administration corrected SMN2 splicing in the spinal cord and lead to a marked increase in SMN protein levels, the treatment only extended median survival to 16 days. In contrast, systemic therapy using two SC injections increased median survival to 108 days. Combining an ICV and SC regimen further increased the median survival to 173 days, while giving animals two additional SC injections at P5 and P7 - after the initial two SC injections at P0–P3 - extended median survival to 137 days.

The SMA mice varied in size, but their average weight was low in comparison with SMN2 heterozygous littermates, and they had much shorter tails, the authors continue. While the majority of rescued SMA mice could run and climb normally, they developed necrotic tails and ears, which were quickly lost: this resembles the phenotype of t ype III SMA mice, the team adds. Necrosis could be delayed, however, following ICV or SC administration.

A further study was then carried out to evaluate the effects of increasing repeat doses of systemic ASO-10-27 administered twice between P0 and P3. This confirmed that survival time was dose dependent, with the highest dose leading to long-term survival that was comparable to the best results previously reported using adeno-associated expression of the SMN protein in a less severe SMA model. In fact, four out of 32 mice treated systemically (with two injections between P0 and P3) at the two highest ASO-10-27 doses were still alive and active after 500 days.

SC therapy in addition resulted in a dose-dependent rescue of ear and tail necrosis, and delays in the development of cataracts and rectal prolapsed. Animals receiving the highest dose of ASO-10-27 had significantly longer tails. Interestingly, adding in two additional SC injections at P5 and P7 only moderately increased survival, “emphasizing the importance of early postnatal therapeutic intervention,” the authors stress.

Analysis of RNA from subcutaneously treated animals confirmed there was a dose –dependent increase in exon 7 inclusion in the spinal cord, brain, liver, heart, kidneys and skeletal muscle – the strongest effect was seen in the liver. Immunoblotting of spinal cord, liver and heart tissue samples from mice treated by SC administration showed a corresponding increase in full-length SMN protein. Exon 7 inclusion in the liver did decrease significantly after P30, but this was consistent with the 20 day half life measurement for ASO in liver. It also emphasizes “that transiently increasing SMN expression in peripheral tissues during the first few weeks of life has a profound effect on long-term survival of severe SMA mice,” the team adds.

In contrast, while ICV administration of the ASO led to more marked changes in exon 7 inclusion in the brain and spinal cord tissues, it had very limited effects in peripheral tissues. The researchers did find that some ASO accumulated in spinal cord motor neurons after SC administration as well, and there was evidence of moderate SMN2 splicing changes in the CNS. This probably reflected “incomplete closure of the blood–brain barrier in neonates and/or retrograde transport of the ASO,” they note, and also probably contributed to the extended survival.

However, the investigators point out, the, “striking effects of systemic administration on survival in this severe mouse model cannot be explained solely by a direct effect on SMN2 splicing in the CNS.” Histological examination of SMA-affected tissues and organs in mice given systemic ASO-10-27 at the highest dose confirmed that therapy led to marked benefits spanning a number of tissues. Both spinal cord α-motor neuron counts, and heart wall and septum measurements in treated mice were comparable to those of the control heterozygous littermates. Average muscle fibre cross-sectional area also reached 80% of that in heterozygotes, while neuromuscular junction integrity was similar in mice treated with the highest ASO dose to that in the control littermates.

Encouragingly, there was also a dose dependent benefit of SC ASO-10-27 therapy on motor function: even though three month old mice that had received the two highest doses of ASO didn’t perform as well on a rotorod test as their heterozygous littermates, they still performed better than SMA animals receiving lower doses of the ASO. Some of the ASO-10-27-treated mice also passed a 30 s acceleration-profile test that many of the heterozygotes failed, the researchers remark. At both five and nine months of age the treated SMA mice demonstrated a forelimb grip that was 80% as strong as that of control mice, while behavioural tests also showed no major difference between treated SMA mice and control animals.

Severe SMA mice tend to be small in relation to wild-type mice, and SC administration of ASO-10-27 has a particularly marked effect on SMN2 splicing in the liver, which contributes about 75% of the circulating IGF1 (a neurotrophic factor that is also involved in cardiac development and function), Dr. Krainer et al note. These observations prompted the team to look specifically at the effects of ASO on the growth hormone (GH)-IGF1 axis.

While IGF1 was either absent or greatly reduced in serum samples from untreated SMA mice, animals receiving SC ASO-10-27 demonstrated normal IGF1 levels. The lack of IGF1 in SMA was found not to be due to a reduction in hepatic Igf1 messenger RNA, but rather was caused by a disease-related reduction in expression of the Igfals gene. Igfals codes for an IGF-binding protein that is stimulated by GH postnatally to bind IGF1 and form a stable complex, which extends IGF1 half life from 10 minutes to 12 hours. Again, SC administration of the ASO rescued Igfals expression in the liver.

“Because Igfals expression is decreased on P1, when the pups are still healthy, we propose that the early deficiency in circulating IGF1 may be one of the factors that contribute to the pathogenesis of severe SMA mice,” the authors state. Indeed, they note, disruption of the IGF1 system is a common feature of neurodegenerative diseases, and Igf1-null mice demonstrate some phenotypic similarity with SMA mice. “Moreover, dysregulation of the IGF1 receptor and its downstream signalling pathway has been observed in patients with type I SMA.” They suggest the latest studies in mice idnicate that “the liver is important in SMA pathogenesis, underscoring the importance, of SMN in peripheral tissues, and demonstrate the efficacy of a promising drug candidate.”

http://www.genengnews.com/gen-news-highlights/antisense-therapy-improves-lifespan-and-motor-function-in-mice-with-severe-spinal-muscular-atrophy/81245788/

SMA breakthrough 'could have implications for a number of conditions'

2011-09-28T09:42:00.005-05:00

SMA breakthrough 'could have implications for a number of conditions'

Healthcare News
27/09/2011
Research into spinal muscular atrophy (SMA) has uncovered certain processes which occur in individuals with the condition.

The debilitating and terminal disease spinal muscular atrophy (SMA) can leave patients in need of assisted living.

A team of scientists from the University of Missouri have now got a further insight into the disease, potentially helping those with the condition.

The study identified a communication breakdown between nerves and muscles in mice.

Critical communication occurs where nerves and muscles 'talk' to each other, explained associate professor Michael Garcia.

If this communication does not happen, muscles cannot work properly.

"In this study, we found that delivery of 'the words' a nerve uses to communicate with muscles was disrupted before they arrived at the nerve ending," said Mr Garcia.

SMA is caused by a protein deficiency in all cells, including motor neurons.

Study authors believe this discovery could also help give scientists further information on other conditions which involve motor neurons, such as amyotrophic lateral sclerosis, and dysfunctions of the synapses, including Duchenne Muscular Dystrophy.

Mogul Using $100 Million in Race to Cure Daughter Lures Novartis

2011-09-07T09:33:00.000-05:00

Reposting an article shared by Tom as a comment to one of the articles.

Mogul Using $100 Million in Race to Cure Daughter Lures Novartis

Tuesday, September 6, 2011

Sept. 7 (Bloomberg) -- Goldman Sachs Group Inc. partner Dinakar Singh discovered in 2001 that his 19-month-old daughter, Arya, had a crippling genetic disease called spinal muscular atrophy.

The malady makes the nerve cells that control muscles gradually deteriorate. There are no treatments, let alone a cure, Bloomberg Markets magazine reports in its October issue. Worse still, while the gene causing the ailment had recently been discovered, nobody in the drug industry was doing much about it, he says.

"I was fearful and anxious that treatments would be developed, but far too late to save Arya," says Singh, 42, who founded and runs New York hedge fund TPG-Axon Capital Management LP, which has $8.1 billion in assets. "We didn't want to find out 25 years later that the science was really there but there isn't a drug because nobody focused on it."

Singh, who left Goldman in 2004, has spent almost $100 million of his own money to create and fund the Spinal Muscular Atrophy Foundation. He wants to discover and develop a drug that he hopes will help his daughter, who is one of 25,000 SMA patients in the U.S. Children with severe forms often die within a few years, while those with mild cases can live a normal life span with supportive care. Arya, 11, and starting sixth grade, uses a wheelchair.

'High-Speed Initiative'

Singh's foundation is making progress. It's collaborating with Novartis AG, which may bring a drug into human tests as soon as 2013, says Mark Fishman, research chief for the Basel, Switzerland-based drugmaker.

The foundation has pumped $13 million into PTC Therapeutics Inc. in South Plainfield, New Jersey, which has produced a pill that increases the life span of mice with SMA. It also has funded a scientist whose research has led to an injectable drug developed by Isis Pharmaceuticals Inc. of Carlsbad, California. That treatment may enter human trials before year's end. Singh says he'll enroll Arya if that drug gets to the testing phase before others.

"The SMA Foundation has converted this from a slow-moving exercise to a high-speed initiative," says Darryl De Vivo, a pediatric neurologist at Columbia University Medical Center in New York, who has overseen Arya's care since her diagnosis.

Frustrated with the sluggishness, or nonexistence, of medical research, Singh and a small band of wealthy parents whose children have serious illnesses are spending millions of dollars to fund drug development.

'Change the System'

These benefactors include hedge-fund managers, private- equity investors and entrepreneurs, many of whom have made their fortunes on Wall Street. The principles they apply in their jobs -- managing complicated tasks, making investments and expecting positive results -- translate to their new endeavors, says Stacy Palmer, editor of the Chronicle of Philanthropy.

"Business executives have a better understanding of how markets work and have started to ask tougher questions," Palmer says. Their goal: "Change the system and whatever is slowing it down."

The new philanthropists are building on a foundation laid by well-known predecessors. John D. Rockefeller in 1901 formed the medical research institute that would become New York's Rockefeller University after his grandson died of scarlet fever. Billionaire Michael Milken, who pioneered junk bonds, founded the Prostate Cancer Foundation and FasterCures, a think tank to speed progress toward cures in all medical fields.

'Lots of Shovels'

Microsoft Corp. co-founder Bill Gates and his Bill & Melinda Gates Foundation have focused on malaria, polio and other global health threats. James Simons, founder of hedge fund Renaissance Technologies LLC, and his wife, Marilyn, started the Simons Foundation. It's the second-biggest funder of autism research, after the U.S. National Institutes of Health, according to recent data.

Benefactors such as Singh are taking a direct role in early drug research. They want to make it easier for companies to produce a medicine or venture firms to fund it. They begin with basic research discoveries, often in obscure illnesses, and advance the work. Instead of handing money to scientists and getting out of the way, they stay involved, hire experts and push researchers to work together rather than compete.

"We have focused on having lots of shovels ready and having the maps ready and having all the supplies ready, so companies are willing to prospect for SMA drugs," Singh says. His idea: "Make it easy for companies, take the risk down for them so they can get a sense cheaply and easily whether there is something there."

Arya's Efforts

Even Arya is doing her bit. In her family's 11th-floor condominium that looks north over New York's Central Park, she says she's excited about holding a bake sale to raise money for SMA research. She has just returned from precautionary tests to make sure a respiratory infection didn't become serious. Her mother pats her back when she coughs weakly. Then Arya scoots off in her wheelchair to play with her younger brother and sister.

James O'Sullivan, director of foundation services for Rockefeller Philanthropy Advisors, says about half of his 25 medical philanthropy clients at any time are interested in the hands-on approach Singh's foundation is taking, up from a handful 15 years ago.

"There is a world of difference between 10 years ago and now," says O'Sullivan, whose New York-based organization advises wealthy patrons. "Today's donors are much more interested in seeing how their dollars make a difference in a disease."

New Breed

Victoria Jackson, a cosmetics entrepreneur whose husband, Bill Guthy, co-founded direct marketer Guthy-Renker LLC, is among the new breed. Her daughter, Ali, came down with a central nervous system disorder at age 14 called neuromyelitis optica, which can cause blindness.

Since then, Jackson has spent more than $15 million on her foundation to develop treatments. Ali, now 18, has avoided severe complications by taking immunosuppressants.

Jackson says scientists often work independently with their own agendas, wasting money.

"I manage where every dime goes and make sure there is complete disclosure and collaboration among the researchers," she says.

Private Investors

Private investors may become crucial as drugmakers cut research and close labs, O'Sullivan says. Pfizer Inc., the world's largest drugmaker, will spend $6.5 billion to $7 billion on research in 2012, down from $9.4 billion in 2010. That makes working with a foundation that already has done some of the grunt work attractive.

"Drug companies want to come in later in the R&D process and provide backing for potential therapies that have more evidence behind them than in the past," O'Sullivan says.

Singh says his foundation can focus on the science because it doesn't have to invest huge amounts of time raising money. And with no need to impress donors, the organization can spend on the business of developing lab tests and building the pieces that make it easier for companies to discover SMA drugs.

The foundation's $16 million in research spending last year almost equals the $19 million the NIH spent on spinal muscular atrophy.

Novartis saved years by taking advantage of advances made by foundation-backed scientists and the laboratory techniques they developed to test compounds for SMA. The company was able to focus on screening for drugs rather than diverting staff to basic research, says Daniel Curtis, a research manager at Novartis.

Rich Donors

The SMA Foundation and its academic partners may reap a benefit if a Novartis drug reaches the market and sells well. Singh's foundation could get back a multiple of its spending on the collaboration, says Karen Chen, the organization's chief scientific officer, who declined to give specifics. Any money would allow the foundation to reinvest in science, she says.

As an incentive for Novartis to work quickly, an agreement allows the company to repay nothing if it completes clinical trials fast enough.

Rich donors with a personal stake in a disease, while well- meaning, can divert resources from illnesses that may be closer to a cure or afflict more people, says Arthur Caplan, a bioethicist at the University of Pennsylvania in Philadelphia.

"There can be some kind of distortion of emphasis," he says.

SMA affects 25,000 Americans versus 5.4 million for Alzheimer's disease, according to the SMA Foundation and the Alzheimer's Association.

Head Start

Singh says spinal muscular atrophy is more likely to be treatable than common neurological diseases such as Alzheimer's, whose origin is uncertain. He says he wouldn't have spent as much money if he thought an SMA treatment was a long shot. Scientists already know what causes SMA, giving researchers a head start, he says.

Garen Staglin, a senior adviser at San Francisco-based private-equity firm FTV Capital, is tackling diseases that are more widespread, including schizophrenia. Staglin's International Mental Health Research Organization has raised $135 million for brain research during the past 17 years. It hosts an annual music concert at his Napa Valley, California, vineyard. Dionne Warwick was scheduled to headline a concert in September.

Staglin's son, Brandon, now 39, was diagnosed with schizophrenia in 1990. Staglin was in France on business and got a call that police had pulled Brandon over as he drove erratically.

"He told me he felt like he had lost half his brain," Staglin recalls. "He just lost his ability to think coherently."

'Run Toward It'

Rather than hide Brandon's situation, Staglin acted.

"We decided we had two choices: We could either run away from the problem like too many families with these illnesses," he says. "We wanted to run toward it."

Another effort, Staglin's One Mind for Research, is working with former Rhode Island Congressman Patrick Kennedy to get drug companies and brain researchers to collaborate on treatments for Alzheimer's, autism, schizophrenia and other conditions. This effort is based on the joint-research approach that has long been used in the semiconductor industry.

For Alexander Silver, the motivation is his 4-year-old son, Jackson. Silver, a partner at New York-based private-investment firm P2 Capital Partners, LLC, started the Jackson Gabriel Silver Foundation in 2010 to find a treatment for a rare genetic condition called epidermolysis bullosa. In the disease, a protein that holds skin layers together is missing, and the skin blisters and shears off with any friction. Half of Jackson's body is covered in high-tech bandages that cost $6,000 a month.

Cutting Red Tape

Silver, 34, who has raised more than $400,000 since 2008 and aims for $10 million or more, predicts a good treatment will come if money flows without red tape to the right projects. His foundation -- along with one run by Paul Joseph, a private- wealth broker at Morgan Stanley Smith Barney LLC whose 7-year- old son has the condition -- has backed work at the University of Southern California in Los Angeles. The research has produced a potential drug.

The approach has garnered $26 million in venture capital from Boston-based Third Rock Ventures to form a company and move the therapy in human trials.

No Budget on Life

"The skills I developed professionally matter a lot for this," Silver says. "Just like investing, you are allocating capital to the projects that have the highest probability of success and the lowest probability of failure in the quickest time frame."

For Singh, the effort to save Arya is a family affair, and he promises to spend as much money as necessary. Singh's wife, Loren Eng, has a Master of Business Administration from Stanford University and works fulltime leading the foundation.

The eight-member staff includes former researchers from Roche Holding AG and Pfizer.

While Arya has a mild form of SMA, she has gotten weaker. She has trouble lifting her arms above her head and needs fulltime nursing. Every cold is a threat because her frail lung muscles put her at risk for pneumonia.

"I don't think there is a budget on your daughter's life," Singh says. "As long as there is a chance of doing something and we have the ability to do it, we will do it."

'In Tears'

Singh, who won't disclose his compensation, says his fund returned 60 percent in the six-and-a-half years since he started it on Feb. 1, 2005. That's more than double the Standard & Poor's 500 Index's 25 percent return during the period.

Arya, the oldest of Singh and Eng's three children, was born in March 2000 and developed normally at first. She was slow to walk, however, taking her first wobbly steps at 15 months. Within months, she began regressing. A doctor friend saw Arya's stiff gait at a party in August 2001 and told them to get it checked out right away.

Eng had become pregnant again, and two days before her delivery date, she got an abrupt call from the neurologist confirming the worst about Arya.

"Loren called me in tears," Singh remembers. "I was saying: 'What does it mean? What does it mean?' She said the doctor didn't say anything. She has SMA. That's it." Singh and Eng spent the next days in a frantic race to figure out the prognosis -- and to discover whether their second child, Kiran, also had SMA. He didn't.

'Untreatable, Incurable, Fatal'

"When we found out about it, we were told it was untreatable, incurable and fatal," Singh says.

De Vivo, the Columbia University neurologist, met the couple and explained that children like Arya have defects in or are missing a gene called SMN, discovered only in 1995. It directs cells to make a protein necessary for neurons that control muscles.

He introduced them to Columbia colleague Thomas Jessell, a motor neuron biology expert. They also met Gerald Fischbach, a neuroscientist and then dean of Columbia's health sciences and medicine faculty. All three became key advisers to the SMA Foundation.

"I met them and decided that SMA was a perfect disorder to mount a major attack on," says Fischbach, who's now scientific director for the Simons Foundation Autism Research Initiative. "The science was ripe."

'Truly Solve It'

At first Singh and Eng had planned to back existing charities, such as Families of Spinal Muscular Atrophy. They gave $750,000 in May 2002 to fund a clinic at Columbia. In 2006, they agreed to give as much as $15 million to help fund a motor neuron research center at the university.

The more they learned, the more they became convinced that, unlike most neurological diseases, SMA might be conquered.

"What struck us as different about SMA was that there really seemed to be a chance to truly solve it -- and perhaps even in a time frame that could really help Arya," Singh says.

A quirk in the genetics of SMA increased their hope. In many inherited diseases, a crucial gene is missing or defective and the protein it makes is absent or doesn't work. In SMA, the body has a backup gene that produces small amounts of the SMN protein. That's why children with the disease live at all.

By the time Singh and Eng became involved, an idea with potential to help SMA sufferers was already being discussed in the medical literature: If someone could find a chemical that could safely boost the availability of the backup protein, that discovery could form the basis of a drug. Yet as far as they could tell, no large drug or biotech company was focused on SMA.

'Terrible Gap'

"You had this terrible gap," Singh says. "There was no one saying, let us take these interesting discoveries and come up with something that could be a drug."

The couple started the foundation in 2003. Equipped with PowerPoint presentations that showed why SMA was a lower research risk than most genetic diseases that could yield a drug with $1 billion in annual sales, they approached more than a dozen companies. It was a hard sell.

At the American Academy of Neurology conference in 2004, only three of seven biotech companies they invited showed up.

"There was never an outright no," Eng says. Instead, "polite conversations went nowhere or calls were not returned."

To her, it seemed drugmakers were focused on heart disease, cancer or diabetes and their significant commercial markets. The NIH alone spends $5.8 billion a year on cancer research.

'A Buzz'

Singh and Eng started paying small biotech companies to screen for chemicals that might increase the supply of the SMN protein. They, along with other SMA charities, also funded Adrian Krainer, a researcher at Cold Spring Harbor Laboratory on Long Island in New York. He was working on a technology that had shown some promise, even though the foundation's scientific advisers said the approach was a long shot.

"There was a buzz; there was this new couple, they are very wealthy, people thought they were in a position to make a difference," says Krainer, who met Arya in 2002 when she could still walk.

For the next few years, the foundation backed research testing dozens of existing drugs to see if any of them increased the SMN protein. The scientific advisers got together in 2008 for a meeting at the Ritz-Carlton hotel in Half Moon Bay, California.

"It was the most-depressing meeting ever," Eng recalls. "It was clear we had nothing."

'Huge Implications'

By then, Arya was in a wheelchair. At this point, the SMA Foundation had captivated Novartis. In 2002, the company had appointed Fishman, a scientist and former Harvard Medical School professor, to direct research operations.

He says one idea was that success in treating rare genetic diseases might pave the way for dealing with more-common ones. Columbia's Jessell and Fischbach pitched him on SMA in 2005.

"It seemed tractable from a scientific point of view, with potentially huge implications on health," Fishman says. "Others weren't working on it, which is another good reason to do it."

Still, it wasn't until November 2007 that Novartis began its effort. It started with neurobiologist Rajeev Sivasankaran and a few assistants. Sivasankaran, 41, designed a quick way to test the more than 1 million compounds in Novartis's collection of chemicals to see if any had potential for SMA. A compound with some modest effect could become a starting point for a safe and effective medicine.

'Full-Court Press'

Novartis was lucky. By December 2009, the researchers had found a drug that improved motor function in mice with SMA.

"That got the whole group excited," Sivasankaran says. The SMA Foundation and Novartis scientists get together every three months to review progress. At a June 1 meeting, researchers from the foundation, Novartis, Columbia and Harvard crowded into a conference room to hear the latest results.

"It is a full-court press," Fishman says. "We are pushing as hard as we can."

Still, Novartis human trials are two years off at best, Fishman says.

Meantime, Repligen Corp., a Waltham, Massachusetts-based biotechnology company, in July began an initial safety test of its SMA drug on people. It licensed this drug from the charity Families of SMA, based in Elk Grove Village, Illinois.

More Efforts

Singh's foundation is closing in with two more efforts. PTC Therapeutics last year found compounds that boost the life span of mice with the disease. The company could begin human trials in late 2012, Chief Executive Officer Stuart Peltz says.

"It is absolutely incredible," he says. Mice that would otherwise barely be able to move look normal with PTC's drug, he says.

Singh and Eng say they're particularly excited by Isis Pharmaceuticals' progress, based on work by Krainer at Cold Spring Harbor. Isis published data in March showing that its drug could boost motor neuron levels -- and survival -- in mice with SMA. The medicine, which is injected into spaces around the spine, corrects the defect that causes the backup gene to produce too little protein.

"I have been doing drug development half of my life," says Roy Vagelos, former Merck & Co. CEO, who has followed the SMA Foundation's research. "This will be the first time if it works that a family had gotten behind a problem, a genetic defect in their own family, and come up with a solution."

Arya is very aware of her illness and the battles to conquer it, even though she doesn't like to talk about it, Singh says. She often asks her parents what her adult life will be like and why she has to be sick.

"Trying to understand what this all means is a big deal now," Singh says.

Arya's Homework

For a homework assignment last year on Egyptian mythology, Arya imagined a goddess of illness.

"She thinks of cures for sicknesses and puts hints for these cures in people's minds," Arya wrote. "She has a puppy face, puppy paws, human body and is always thinking of cures." Eng sent a copy of her daughter's essay to Novartis's Fishman.

"It hits you right where you live," he says. "That kind of innocent gratitude is the most wonderful reward you can get."

--Editors: Michael Waldholz, Gail Roche, Stryker McGuire

From skin cells to motor neurons

2011-08-29T09:48:00.001-05:00

http://www.physorg.com/news/2011-08-skin-cells-motor-neurons.html

“One of the utilities [of this new method for producing motor neurons] is it makes a much more rapid way to grow motor neurons. This could allow us to test very rapidly whether a new therapeutic is likely to be effective,” said Kevin Eggan, leader of the Harvard team of stem cell researchers that has succeeded in reprogramming adult mouse skin cells directly into the type of motor neurons damaged in Lou Gehrig's disease and spinal muscular atrophy. Credit: B. D. Colen/Harvard Staff

A team of Harvard stem cell researchers has succeeded in reprogramming adult mouse skin cells directly into the type of motor neurons damaged in amyotrophic lateral sclerosis (ALS), best known as Lou Gehrig’s disease, and spinal muscular atrophy (SMA). These new cells, which researchers are calling induced motor neurons (iMNs), can be used to study the development of the paralyzing diseases and to develop treatments for them.

Producing motor neurons this way is much less labor intensive than having to go through the process of creating induced pluripotent stem cells (iPSC, iPS cells), and is so much faster than the iPS method that it potentially could reduce by a year the time it eventually takes to produce treatments for ALS and SMA, saidKevin Eggan, leader of the Harvard team.

Importantly, the direct reprograming does not involve the use of any factors known to trigger cancer or any other disease states, and the factors in fact make the fibroblasts, the connective tissue cells that make and secrete collagen proteins, stop dividing.

The work by Eggan, a member of the Harvard Stem Cell Institute principal faculty and an associate professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), and his colleagues builds on and advances work by SCRB co-chair and Professor Doug Melton, who pioneered direct cellular reprogramming, and Marius Wernig of Stanford, who used direct reprogramming to produce generalized neurons.

In a paper given “Immediate Early Publication” online by Cell Stem Cell, the Eggan team reports that the cells they are calling iMNs appear to be fully functional. “One of the most important things we’ve done is show that when you put them into the embryo they function normally like motor neurons,” Eggan said in an interview. “They move to the right place and function on their own.”

When placed in the spinal cord of a chicken embryo, the iMNs settle into the cord and send out their projections to connect with muscles. “That’s a unique thing,” Eggan said. “We showed [that] they have contact with muscle cells and make synapses with them.”

When the iMNs cells were placed in a lab dish with muscle cells, they made what appeared to be normal contact, Eggan said, “and when we add curare to the dish, that contact stops over time — which is exactly what curare does in nature; it is an antagonist to the receptors on the muscle cells.” Curare, which is used as a paralyzing agent by anesthesiologists, is the substance some South American native people place on the end of darts to hunt game.

“One of the utilities [of this new method for producing motor neurons] is it makes a much more rapid way to grow motor neurons. This could allow us to test very rapidly whether a new therapeutic is likely to be effective,” Eggan said. “Realistically, it takes about a year for us to create an iPS cell line; this [approach] takes weeks.” In the past, producing iPS motor neurons from a patient’s skin cells, and producing them in large quantities, could require the effort of 100 people. “This reduces both the time involved and scale of effort, which is particularly important in these tough economic times, as it obviously also reduces the costs involved.”

Explaining how this success was built on previous discoveries, Eggan said, “We had been taking fibroblasts from mouse embryos, skin cells, and were able occasionally, rarely, … to turn those cells into motor neurons using a set of factors we developed. We were struggling. And at that moment, Marius Wernig came up with a system for what I would call making generic neurons; they were electrically active, they looked like neurons, but they didn’t have the properties you could assign to any neural cell type. But when we combined our factors with his factors, it allowed us to go on and make motor neurons.”

This story is published courtesy of the Harvard Gazette, Harvard University’s official newspaper. For additional university news, visit Harvard.edu.

Provided by Harvard University (news : web)

AMRI gets NIH contract award for development of pre-clinical drug candidates to treat diseases of the nervous system

2011-08-23T09:44:00.003-05:00

AMRI gets NIH contract award for development of pre-clinical drug candidates to treat diseases of the nervous system

Albany, New York
Tuesday, August 23, 2011, 13:00 Hrs [IST]

Albany Molecular Research, Inc. (AMRI) announced it has received a federal contract award from the National Institutes of Health (NIH) / National Institute of Neurological Disorders and Stroke (NINDS) to provide chemistry and other drug discovery technologies in support of NINDS' Medicinal Chemistry for Neurotherapeutics Programme (MCNP), part of the NIH Blueprint Neurotherapeutics Network. AMRI has been collaborating with NINDS since 2005 on novel treatments for spinal muscular atrophy, a degenerative neuromuscular disease.

The five-year contract provides AMRI with funding of up to $43 million, based on the number of approved projects and availability of funds. The initial funding of up to $10 million applies to the first phase of the project, expected to begin this month, with the objective of delivering at least one phase I clinical trial candidate.

“After a highly competitive, rigorous application process, AMRI was selected for this contract award because of our proven track record on projects of similar scope with a number of global pharmaceutical companies. The company's deep bench strength, scale of operations, and strong global footprint enable us to consistently deliver high performance and quality for our clients on a cost-effective basis. This significant award demonstrates the NIH's new focus on helping support the translation of basic research discoveries in areas of unmet medical need to potential drug candidates,” said AMRI's chairman, president and CEO, Thomas E D'Ambra, PhD.

“We are pleased to support NIH/NINDS' efforts and provide our discovery resources to the neuroscience research community and to patients who suffer from devastating neurological and degenerative diseases, such as macular degeneration and Alzheimer's disease,” added Dr D'Ambra.

“The Blueprint Neurotherapeutics Network is modelled after the NIH Spinal Muscular Atrophy (SMA) Project. Our successes in partnering with AMRI and other companies on the SMA Project have given us the confidence to extend this approach to other disorders that affect the nervous system,” said Jill Heemskerk, PhD., a programme director in the NINDS Office of Translational Research and the lead contact for the Blueprint Neurotherapeutics Network.

Under the MCNP, AMRI will begin providing medicinal chemistry services to neuroscientists throughout the United States with the goal of efficiently developing pre-clinical drug candidates that are suitable for advanced development and ultimately clinical trials in humans. AMRI will utilize its integrated drug discovery capabilities involving exploratory chemistry, hit-to-lead chemistry, and lead optimization. Specific services to be provided include compound design, synthesis, and management together with in vitro metabolic testing.

The National Institutes of Health (NIH) is a component of the US Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.

AMRI provides scientific services, products and technologies focused on improving the quality of life.

http://www.pharmabiz.com/NewsDetails.aspx?aid=64656&sid=2

Study offers hope to kids with fatal genetic disease

2011-07-26T14:19:00.000-05:00

http://www.torontosun.com/2011/07/25/study-offers-hope-to-kids-with-fatal-genetic-disease

OTTAWA - Researchers at the Children’s Hospital of Eastern Ontario in Ottawa have made what they describe as a landmark discovery in the fight against spinal muscular atrophy, better known as SMA.

The disease, the infant equivalent of ALS, is a genetic disorder that causes muscle weakness and loss of motor control. In its most severe form, survival of children with SMA beyond the age of five is rare.

The discovery will likely increase the lifespan of afflicted kids and could lead to a cure.

The research report was published Monday in the Journal of Clinical Investigation.

"SMA is the No. 1 genetic cause of death in the first years," said Dr. Alex MacKenzie, principal investigator at the CHEO Research Institute.

MacKenzie and PhD student Faraz Farooq discovered that treating the disease with the pregnancy hormone prolactin over time extends the lifespan of mice with SMA by up to 60%.

"It was completely Farooq's idea," MacKenzie said. "I was sort of dozing at my desk and my graduate student said 'I'm going to try this,' and then he came back and said ,'Look at this.'"

The fact that prolactin is already known to be safe for humans should allow MacKenzie and Farooq to skip several steps in the testing process.

"It's a bit of a perfect storm of something that's already been used clinically and that shows the strongest effect among other agents that have been tested," MacKenzie said before adding that while it's a solid step in the right direction, it's not a miracle cure.

"If you took a child with well-developed SMA whose motor neurons are lost and started giving prolactin therapy, it would stop the disease, maybe offer a slight improvement, but it wouldn't be a cure because those cells are already gone. But if you diagnose in the first weeks of life, then I think this has got very good promise."

The next phase of testing on infants will cost north of $5 million, he said, but the potential of helping kids around the world has him excited.

"We sort of make our careers doing this stuff and then we go and give talks and say how great we are, but if we can actually impact children with this, boy, I'd be one happy individual."

"News of prolactin's role and effectiveness in SMA regulation breathes fresh hope into all of the SMA community," said Martha Slay, the president and co-founder of FightSMA, in a release.

Short story by my daughter

2011-07-18T10:52:00.003-05:00

My daughter who has SMA type 2 wrote this short story. Nothing related to SMA except that I am a proud parent. http://www.amazon.com/Portalia-ebook/dp/B005CWF6NM/

Canadian researchers solve 30-year-old mystery

2011-07-18T09:54:00.002-05:00

PRINCE GEORGE, B.C.—A technical break-through in gene splicing by experts at the University of Northern B.C. may lead to better understanding of genetic disorders such as cystic fibrosis, spinal muscular atrophy and certain types of dwarfism.

UNBC chemistry professor Stephen Rader says it’s a puzzle researchers have been trying to piece together for about 30 years.

Gene splicing involves cutting out part of the DNA in a gene and adding new DNA in its place, changing and repairing the function of the gene.

The UNBC team discovered that a region of the molecule, known as U4, is essential for assembling the splicing machinery.

Up until now, experts had thought the molecule played no role in the splicing process.

The research will be presented at a Western Canada conference on RNA, or ribonucleic acid, being held Monday and Tuesday at the Prince George, B.C., university.

The discovery stems from a component of a master’s project of recent UNBC graduate Amy Hayduk.

Rader noted that they have also discovered a new way to study what the molecule is doing in the test tube.

“We found mutations in U4 that make it better than normal at assembling the splicing machinery, but worse at the actual splicing reaction,” he said in a news release. “It leaves before the actual splicing happens, so it is apparently only there to help put things together.”

Rader said they didn’t don’t understand how or why the molecule acts that way.

“This is as if you were tinkering with the ignition on your car and managed to make the ignition work better, but then discovered that, even though the car starts better, it no longer runs.”http://www.thestar.com/news/canada/article/1026202--canadian-researchers-solve-30-year-old-mystery?bn=1

Repligen gets US fast track status & European orphan medicinal product recommendation for RG3039 for spinal muscular atrophy

2011-06-25T10:06:00.000-05:00

Repligen gets US fast track status & European orphan medicinal product recommendation for RG3039 for spinal muscular atrophy

Waltham, Massachusetts
Saturday, June 25, 2011, 16:00 Hrs [IST]

Repligen Corporation announced that the US Food and Drug Administration (FDA) has granted Fast Track designation for RG3039, a potential treatment for Spinal Muscular Atrophy (SMA). Fast Track is a process designed to facilitate the development and expedite the review of drugs that treat serious diseases and fill an unmet medical need.

Once a drug receives Fast Track designation, frequent communication between the FDA and the sponsor is encouraged throughout the development and review process. In addition, RG3039 has received a positive opinion for orphan medicinal product designation from the European Medicines Agency. European orphan medicinal product designation aims to encourage the development of drugs involved in the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition that affects no more than five in 10,000 persons in the European Union.

“Receipt of Fast Track designation and a positive opinion for European orphan medicinal product designation for RG3039 demonstrates the FDA and EMA commitment to the study and development of treatments for rare and serious diseases,” stated Walter C. Herlihy, president and chief executive officer of Repligen Corporation. “This regulatory support adds momentum to our efforts to develop a novel treatment for patients with Spinal Muscular Atrophy.”

Repligen has received approval from the FDA to initiate a phase I clinical trial of RG3039, the first clinical trial of a novel drug specifically designed to treat SMA and the first treatment approach which seeks to increase levels of the deficient protein SMN. This is a double-blind study to evaluate the pharmacokinetic and safety profile of escalating doses of RG3039 in up to 40 healthy volunteers.

Repligen’s ongoing research efforts are funded in part with grants from the Muscular Dystrophy Association. This programme was licensed in 2009 from Families of Spinal Muscular Atrophy. Families of SMA fully funded and directed the preclinical development work with an investment of more than $ 13 million prior to licensing RG3039 to Repligen. Families of SMA previously secured US Orphan Drug Designation for RG3039, providing important regulatory and marketing incentives for the programme.

The work led by Families of SMA was the very first drug development programme ever done for SMA.

SMA is an inherited neurodegenerative disease in which a defect in the SMN1 (“Survival Motor Neuron”) gene results in low levels of the protein SMN and leads to progressive damage to motor neurons, loss of muscle function and, in many patients, early death. Patients lacking a functional SMN1 gene survive only because humans carry a second gene called SMN2 which produces low levels of SMN protein. RG3039, an orally bioavailable compound, is an inhibitor of an RNA processing enzyme which targets SMN2 and has been shown to increase production of SMN protein in cells derived from patients. In addition, RG3039 has been shown to improve mobility and lifespan in preclinical animal models of SMA. RG3039 is a new chemical entity, which is the subject of worldwide composition of matter patent applications which, if allowed, will remain in force until 2028 prior to any patent term extensions. The prevalence of SMA in the U.S. and Europe is approximately 20,000 patients and there is currently no treatment or cure for the disease.

Families of SMA is a nonprofit 501(c)3 tax exempt organization with 30 Chapters throughout the United States and over 70,000 members and supporters. Families of SMA funds and directs the leading SMA research programs. The successful results and progress from basic research to drug discovery programs to clinical trials provide real hope for families and patients. Families of SMA is dedicated to creating a treatment and cure by: funding and advancing a comprehensive research program; supporting SMA families through networking, information and services; improving care for all SMA patients; educating healthcare professionals and the public about SMA; enlisting government support for SMA; embracing all touched by SMA in a caring community. FSMA’s vision is a world where Spinal Muscular Atrophy is treatable and curable.

The Muscular Dystrophy Association (MDA) is the leading nonprofit health agency dedicated to curing muscular dystrophy, ALS, SMA and related diseases by funding worldwide research.

Repligen Corporation is a biopharmaceutical company focused on building an integrated company by developing and marketing innovative drugs that deliver the benefits of protein therapies in the fields of neurology and gastroenterology.

Stem-Cell Gamble

2011-06-21T10:13:00.002-05:00

Stem-Cell Gamble

After years of controversy, a therapy based on human embryonic stem cells is finally being tested in humans. The treatment holds out hope to paralyzed people, but at how great a risk?

JULY/AUGUST 2011
BY ANTONIO REGALADO

Full of hope: T.J. Atchison was the first patient to be treated with a new approach to mending spinal-cord injuries. The treatment uses cells grown from embryonic stem cells. Credit: Cary Norton

Audio »

Hans Keirstead wakes up every morning at his home near Los Angeles and checks CNN. He's looking for news about the first-ever human test of embryonic stem cells, launched in October by the biotechnology firm Geron. Mostly, he's looking for bad news. "If someone dies, or is in pain, then it's over," he says, pushing a hand through his tawny hair. Keirstead, dressed in a loose linen shirt and wearing a thumb ring, is a biologist at the University of California, Irvine, who has variously been called the "rock star," "miracle worker," and "Pied Piper" of stem-cell science. Today he has a corner office in a new $67 million research center paid for in part by California voters, whom he helped persuade to vote for a $3 billion stem-cell spending plan in 2004 with a video of partially paralyzed rats walking again after stem-cell transplants performed in his laboratory.

That same treatment is now being tested in human beings. No wonder Keirstead is anxious. Although he is not directly involved in the clinical trial, the discovery he patented, promoted to Californians, and later licensed to Geron has now become the leading test of whether embryonic stem cells will finally live up to their medical potential. "I'm dying to know if it works," he says.

As Technology Review went to press, Geron had so far treated two patients: a 21-year-old nursing-school student named T. J. Atchison, who was paralyzed at the chest in a car crash last September, and a second person who has not been publicly identified. The hope is that cells injected into their spinal cords could help mend damaged nerves and restore at least a degree of mobility and sensation. Even if the treatment fails, many researchers believe the test is a critical step toward a time when bodies are healed and regenerated with living cells, not chemical drugs. "Cell therapy is now here to stay," says Wise Young, a professor at Rutgers University and an expert on spinal-cord injury. "I tell my students that this will be the future—that they will be the first generation of doctors to use cell therapy."

Thirteen years of public debate, scientific surprises, lawsuits, and presidential decrees have gone by since embryonic stem cells were first isolated, in 1998. Stem cells drawn from early-stage human embryos have the potential to develop into any type of cell in the body. In a lab dish, they can give rise to nerves, skin, even pulsating heart cells. And Geron, a 180-person biotech outfit in Palo Alto, has promised for a decade that treatments based on the cells could be just around the corner. The company says it spent $45 million on amassing the evidence needed to persuade the U.S. Food and Drug Administration to allow the first-of-a-kind human trial to proceed—an effort that included animal tests it calls exhaustive. "The agency told us our application was the largest they'd ever received," says Geron's interim CEO, David Greenwood, sweeping his hand over a double-length conference table that once creaked under the weight of all 22,500 pages.

Geron's success in getting the FDA to green-light the trial has already triggered a small explosion of other embryonic-stem-cell studies. Advanced Cell Technology, a smaller competitor in Marlborough, Massachusetts, has been cleared to begin two trials that will involve replacing cells in the eyes of people going blind from macular degeneration: lab workers will use stem cells to manufacture a type of retinal pigment cell that the disease kills off. Next in the pipeline is a startup company's effort to transplant lab-grown replacement nerves into infants with a fatal genetic disease called spinal muscular atrophy. That trial is planned by California Stem Cell, which has raised $10 million from wealthy donors and has signed up Keirstead as its chief scientific advisor. Keirstead, bounding through the still empty offices with a tape measure in hand, says he is considering leaving his lab to join the company full time. He thinks that with the Geron trial now under way, other human studies can advance much more quickly and cheaply.

But that depends on what happens in the Geron trial. And even some of stem cells' most ardent advocates worry that things may be moving too fast. Arthur Caplan, a bioethicist at the University of Pennsylvania and a defender of stem-cell research (see Q&A,September/October 2006), calls the Geron study poorly designed and says it should never have been allowed to proceed. "This is nuts and hugely risky," says Caplan. "The animal studies are not adequate to justify the trial." Those studies provide too little proof of safety, he contends, and Keirstead's original findings in rats offer thin evidence that people will be helped.

Looming large is the history of gene therapy, another advanced biomedical technology, which badly misfired when a young volunteer named Jesse Gelsinger died in a safety study in 1999. Caplan, who was close to those events, sees worrisome similarities (see "The Glimmering Promise of Gene Therapy," November/December 2006). "If they get an adverse event, there will be hell to pay," he says.

NO MIRACLE

Spinal-cord injuries cause paralysis by killing off nerves that transmit sensory impulses and leaving others stripped of their myelin sheath, the layer of fatty insulating material that helps nerve signals travel. Geron manufactures its treatment, known as GRNOPC1, by coaxing embryonic stem cells to form what are known as oligodendrocyte precursor cells. Those cells are bottled and frozen, and Geron scientists believe they may help restore some degree of sensation and limb movement to patients if transplanted soon after a spinal-cord injury. That is because oligodendrocyte cells produce myelin and may serve other purposes as well, such as encouraging new blood vessels to form. In Geron's initial human trial, designed to test the safety of the treatment, doctors plan to inject two million cells each into the spines of 10 people whose legs have been paralyzed in accidents.

Credit: Associated Press (Bush); Frazer Harrison/Getty Images (Prop. 71); Associated Press (Geron); Larry Downing/Reuters (Obama)

Will the treatment be a cure? The odds are against it. In general, most new treatments, never mind highly experimental ones, bomb out early. What's more, GRNOPC1 faces an uphill fight against medical dogma, which says that it's impossible to reverse damage to either the brain or the human spinal cord. That means few experts expect a miracle from GRNOPC1. Richard Fessler, a surgeon at Northwestern Memorial Hospital in Chicago who is leading patient recruitment for the Geron trial at seven U.S. medical centers, calls the study a "rational" attempt to reverse spinal-cord damage. But he cautions against expecting too much. "We wouldn't be doing this if we didn't have hope, but I don't want to instill false hope," Fessler said in a news conference in May, after the second patient received the treatment. "I'm not going to go to one of these patients and say, 'We're going to give you a transplant and you're going to walk.'"

Still, some patients are clamoring to join the Geron study, even though only people with extremely recent injuries—the kind that lab research suggests might be helped—are allowed to participate. A Dutch man offered Geron $1 million to treat his son, and Keirstead says he received an even bigger offer from a paralyzed Texas millionaire. "He said he'd pay me whatever millions it takes to set up a clinic in Mexico, and another $2 million for me, just to treat him," he says. "It made me pause, but not for long."

One person who made a public plea to enter the trial is Michael Martinez, a 24-year-old jockey who was paralyzed after falling from a horse at San Francisco's Golden Gate Fields last year. Martinez was refused, in part because his injuries, including three crushed vertebrae, were too extensive. "He is the most challenging candidate for stem cells—if they can have any impact in him, that would be extraordinary," says David Seftel, the doctor who came to Martinez's aid at the track and has led a campaign to have him treated with stem cells. Seftel complains that the spinal-cord specialists who treated Martinez view stem-cell research with skepticism and were reluctant to get behind the idea. "We experienced a lot of resistance," he says. "We were told it's an irresponsible option to present to patients at this time. But the science only advances if people take carefully calculated risks."

With Seftel's help, and a letter-writing campaign by other paralyzed people, Martinez is now a candidate (pending Swiss government approval) to join a study in Switzerland sponsored by a California company called StemCells Inc. In that study, doctors are implanting nerve cells obtained from early-stage human fetuses; unlike embryonic stem cells, such fetal cells have already begun to differentiate into other cell types. "We have moved heaven and earth here to make sure he gets in," says Seftel. If he's approved, Martinez will travel to Switzerland for screening and then, if he passes, undergo 30 days of additional tests before being cleared to participate in the trial.

Martinez, a Panamanian who speaks little English, says he believes the operation "could help me regain sensation in my legs, and return to capacities I had before." As with most paraplegics, being unable to walk is the least of his problems. His biggest difficulty is bladder infections, since he must urinate through a catheter. Martinez says he's aware that there are dangers associated with the stem-cell treatment, but as a jockey, he's used to long odds. "I know it has certain risks, but I don't want to think about those," he says. "I want to stay focused on the positive."

TOO POWERFUL

The human embryonic stem cell was isolated in 1998 by James Thomson at the University of Wisconsin (Geron, in a farsighted gamble, funded his work). Thomson made two main scientific claims about his discovery. The first, and better known, involved the cells' capacity to differentiate into any tissue type in the body. Less well understood but equally important was that embryonic stem cells are immortal: they keep dividing, never running down as normal cells do. They are, in short, like no other human cells.

The truth of those claims is evident at Geron's one-story headquarters in Palo Alto. In its labs, the company grows not only nervous-system cells but also heart muscle, which is being transplants into 100-pound pigs, and cartilage cells that are being tested in the knees of sheep. Amazingly, all the billions of cells that Geron has grown for its spinal-cord program—including those injected into Atchison's spine—are direct descendants of the very first supply of stem cells that Thomson created from an embryo, a cell line known as H1. "There is no further destruction of human embryos required to keep this work going, and there hasn't been since 1998," Ed Wirth, Geron's medical director, told a Phoenix audience last year. "[It's] very, very powerful how you can multiply these cells."

Watching closely: Biologist Hans Keirstead, a self-proclaimed optimist about stem cells, says he is now anxiously awaiting the results of human tests. Credit: Cary Norton

If anything, embryonic stem cells are too powerful. Early on, scientists hoped they would be magic bullets for a variety of diseases. Just inject them—and watch them race to injury sites and fill in for dying cells. In one early study, embryonic stem cells placed in the brains of rats suffering from symptoms of Parkinson's disease did precisely that. Not only did the cells become new neurons, but they began to squirt out dopamine, the chemical lost in Parkinson's. The problem was that they often ran amok, multiplying into frightening tumors called teratomas—disorganized mixtures of tissues, such as teeth, hair, and jawbone. Rats that developed such tumors died.

The brain tumors were a sign that the stem cells were still attempting to carry out their original mission: to form an entire person. Researchers quickly settled on a new strategy. They would use stem cells, but only to manufacture daughter cells restricted to a particular destiny—cells already committed to becoming liver, say, or new muscle. "No one wants to put embryonic stem cells into humans, only the product," Keirstead explains today. What he worked out at his Irvine laboratory was a recipe for turning embryonic stem cells into relatively pure populations of oligodendrocyte precursors. It's not easy: his recipe requires 42 days of coaxing, coddling, and adding growth factors at just the right moment. Then, in 2005, Keirstead published a report saying that when he injected the oligodendrocyte cells into the spinal cords of crippled rats, they went from dragging their hind paws to walking again in a matter of days. That result was a bombshell, and Geron, which has poured $1.8 million into Keirstead's lab, quickly decided that pursuing a stem-cell treatment for people with spinal injuries would become the company's flagship program.

One of Geron's challenges has been to create an industrial recipe for growing the large numbers of cells needed for treating patients. The company's senior director for manufacturing operations, Sean Cullen, says Geron is now, with its technology, where companies such as Amgen and Genentech were with protein and antibody drugs a decade ago, when they began manufacturing them. But if proteins were harder to make than ordinary chemicals, cell therapy is an order of magnitude more difficult still. "Think about it," Cullen says, pointing through a glass porthole into the clean room, where the cells multiply in jars of pink medium. "The cell is a living thing—you can't define what it is with the same granularity." Indeed, the product that Geron makes can't be characterized like a chemical compound. Rather, it's a mixture of different types of cells, including oligodendrocytes. The manufacturing process is in many ways still undefined, Cullen says—still an art. When he heard that cells he'd cultured had been injected into someone's spine, "that brought it home," he reflects. "Now you know it's life and death."

RISKS VERSUS REWARDS

What worries some scientists is that Keirstead's results in rats have never been independently confirmed and published. That's not unusual in science, but it may be reason for caution in this case, since many discoveries in the stem-cell field have later unraveled. "I do think it matters if it is replicated," says Thomas Lane, a neuroscientist at the University of California, Irvine, who once collaborated with Keirstead to use the cells in mice with symptoms of multiple sclerosis, only to find that the cells didn't survive and did not appear to produce new myelin. While the two studies can't be compared head to head, says Lane, "at the end of the day [the cells] didn't work for us."

One complication in trying to reproduce the results is that other labs may begin with different populations of embryonic stem cells, and each lab has its own tricks for inducing the cells to differentiate, which makes direct comparisons difficult. Wenbin Deng, a professor at the University of California, Davis, has tried to replicate Keirstead's recipe, and the results leave him cautious about human tests. "I think it's still a little bit premature at this point," Deng says. "Even though this type of cell is ideal for transplant studies, there is still a lot of uncertainty about their safety and efficacy."

Geron scientists say they have replicated and extended Keirstead's findings, although the data haven't been published. "We would like to publish, but that is not the focus of the team," says Anna Krassowska, a stem-cell scientist who now works as Geron's director of investor relations. "Sometimes there is the perception that our entire trial is based on the seven rats of Hans Keirstead, and that is not true."

Yet even if the treatment heals rats, it is still unclear exactly what it does. Originally, the theory was that new oligodendrocytes should restore the missing myelin on axons, the projections of nerve cells that transmit electrical signals. But Ann Parr, a spinal surgeon and researcher at the University of Michigan, says the benefits appear so quickly—in a matter of days—that new myelin can't be the whole story. Maybe the cells emit chemicals that help prevent ongoing damage in some other way. "I think there is pretty good evidence that transplanting the cells can have a beneficial effect, but nobody knows how they work," says Parr.

For critics such as Caplan, the caveats add up to serious doubts. He says he doesn't see a reason for human tests given the "unimpressive" results in rodents, whose injuries were not as severe as those of Geron's human subjects. What's more, the patients Geron is treating aren't terminally ill. People who are paralyzed in accidents often adapt after the initial shock and return to relatively normal lives. "At first you think they don't have much to lose," Parr says, "but they actually do. They could die." None of those concerns weighed too heavily on Atchison, Geron's first patient. He signed the forms to join the trial only 30 minutes after reading them. Since the injection, Atchison has worried more about the prospect of developing a tumor, but he has come to terms with the danger. "Even if I became sick," he says, "I would still be contributing to the health of someone else, somewhere down the line" (see "The Right Decision").

Looking ahead: Atchison, shown here at his home in Chatom, Alabama, says he sometimes worries about the dangers of Geron’s new treatment but has faith that his participation in the clinical trial will help others. Credit: Cary Norton

The job of balancing the evidence for and against stem-cell therapy fell to the U.S. Food and Drug Administration in 2008, when Geron first submitted its application to test the treatment in people. For the agency, which is charged with ensuring the safety of all medicines, embryonic stem cells were not only a charged political subject but a huge technical challenge. When the FDA called together its top advisors that year, at the Hilton Hotel in Gaithersburg, Maryland, to discuss whether to approve Geron's treatment, one participant called stem cells "probably the most complex biological therapeutic humanly imaginable."

Everyone was well aware of how some previous attempts to alter the body's cellular and genetic makeup had gone wrong. In addition to the infamous gene-therapy death, there was the case of Parkinson's patients who began to experience uncontrolled movements after receiving transplants of tissue from fetuses. Also worrying was a French study a decade ago in which transplants of genetically altered bone marrow had cured children of severe combined immunodeficiency, or "bubble boy" disease, only to cause leukemia years later. Unlike ordinary drugs, whose action quickly fades, these treatments threatened to get stronger. "For some products," agency officials noted, "unchecked proliferation is a real possibility."

The FDA's overriding worry was that a stray embryonic stem cell could cause a tumor. After the 2008 meeting, the agency told Geron that its trial couldn't proceed. The problem: some of Geron's rats had developed tiny cysts where the treatment had been injected. Jane Lebkowski, Geron's chief scientific officer, says the growths were harmless masses of epithelial cells, like "microscopic water balloons." Harmless, maybe. But they didn't belong in the spinal cord, and who knows how much they might grow during a human lifetime. Lebkowski says Geron adjusted its manufacturing recipe to eliminate the unwanted tissue. But it took the company another two years—and a hundred or so more rats—to persuade the FDA that its product was safe enough to test in people. Even so, the FDA demanded unusual safety precautions—stipulating, for example, that the patients be tracked for years to come.

Such delays add up, and some believe the FDA is creating a roadblock. Several companies have gained the agency's approval to test injections of stem cells taken from immature human fetuses, an older but related technology that has also raised concerns at the FDA. "The problem is that the agency is overworked and understaffed and isn't so familiar with cell therapy," says Richard Garr, CEO of NeuralStem, a company that recently began tests of fetal spinal-cord cells in patients with Lou Gehrig's disease, or ALS. For NeuralStem's study, like Geron's, the agency required that patients be treated at least 30 days apart, to allow time to tell whether problems would arise. It will take the company at least a year and a half to complete the study, given that 18 patients are expected to enroll. "And here is a disease that kills you in three to five years, on average, after diagnosis," says Garr. "So it feels like they are slowing you down. I think the FDA believes the caution is justified. I can tell you that the patient advocacy groups are frustrated."

Indeed, many patients opt not to wait. Unregulated clinics, cranks, con men, and quacks have popped up from Cancún to Beijing, tempting patients to pay as much as $40,000 for the chance of a stem-cell miracle. But medical tourists who dodge U.S. safety regulations for overseas injections run unknown risks. In 2009, Israeli doctors treating a 13-year-old boy reported the first case of a brain tumor caused by a stem-cell therapy. The boy's parents had taken him to a fly-by-night Moscow clinic where cells gathered from human fetuses had been injected into his brain.

Patients who join the Geron study, by contrast, will be subject to a battery of MRIs, blood tests, medical exams, and follow-ups lasting 15 years. Perhaps because of the demands put on candidates, the trial has been moving at a crawl. In April, the company surprised investors when it reported that in six months it had managed to enroll only one patient. The good news was that the patient, Atchison, had suffered no unexpected side effects. The bad news, even after the second patient was enrolled in May, is that at this pace it will take Geron an agonizing three years to finish. CEO David Greenwood says that the company has asked the FDA to loosen the strict criteria for subjects. "Cell therapies are new, and the agency appropriately, I think, takes a very conservative posture," he says. But, he adds, "you can narrow your funnel so much you don't get any patients."

Back at his office at UC Irvine, Keirstead says he has received several phone calls from people who were considering joining the Geron trial: "They were looking for a level of confidence, a feeling from me. Is it really going to work, and is it safe?" The calls have put Keirstead in a difficult spot. "My ridiculous sense of optimism may be clouding my judgment," he says. "But I tell them we've done everything we can possibly do scientifically and in animals. And we still don't know if it works in humans."

Antonio Regalado is the Latin America contributor to Science magazine. He is based in São Paulo, Brazil.

Soldier Re-Grows Leg Muscle After Experimental Procedure

2011-06-20T13:06:00.000-05:00

From Slashdot. A remotely related topic.

Marine Isaias Hernandez has been able to grow back most of the missing muscle from his leg, including skeletal muscle, thanks to an experimental treatment involving an injection of a a growth promoting substance extracted from pig bladders. Hernandez lost 70% of his right thigh muscles from a mortar exploded attack in Afghanistan. Normally this type of injury would lead to an amputation. From the article: "In preparation for the operation, corporal Hernandez was made to build up the remaining 30 per cent of muscle left on the damaged thigh. Surgeons then sliced into the thigh, placing a thin slice of a substance called extracellular matrix. The surgery is the result of a $70 million investment by the US military into regenerative medicine research."

CIRM to Give $25M for First Human Stem Cell Trials, Keirstead's Novel Spinal Cord Therapy to be Tested in Damaged Spines Read more: http://www.sfgate.com/cgi-bin/article.cgi?f=/g/a/2011/05/06/prweb8390942.DTL#ixzz1LaFZk5Yx

2011-05-06T09:45:00.000-05:00

Irvine, CA (PRWEB) May 06, 2011

The California Institute for Regenerative Medicine (CIRM) has announced that it will give $25 million to a clinical trial that will test an embryonic stem cell-based therapy for spinal cord injuries. The trial is the first to test a therapy based on human embryonic stem cells.

Hans Keirstead, PhD, UC Irvine Professor of Anatomy and Neurobiology at the Reeve-Irvine Research Center, and Chairman of the Scientific Advisory Board of California Stem Cell (CSC) led the team that came up with the novel treatment. It involves injecting human embryonic stem cell-derived spinal cord cells into a damaged spine.

Because of CIRM rules, the company running the trials can not be disclosed. Said Keirstead, "This is a great day and an amazing leap forward for the science and potential of stem cells. I hope that it will change the future of spinal cord injuries and diseases. UC Irvine and California Stem Cell are not running or responsible for the clinical trial outcomes, but you can be assured that we will be following the study closely, and look forward to great progress."

The money from the California Institute of Regenerative Medicine comes from Proposition 71, which voters approved in 2004.

ABOUT CALIFORNIA STEM CELL

Founded in 2005, California Stem Cell is to catalyze the efficient development of human therapies based on human embryonic stem cells. CSC has developed proprietary methods for scalable production of human motor neurons, neuronal progenitors, hepatocytes, and cardiac cells, at high purity, from hESCs.

CSC is currently developing stem cell based therapies for spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS, or Lou Gehrig's Disease). CSC also markets high-purity human cells in platforms suitable for high throughput and high content screening of conventional drug candidates using human cell substrates, predictive toxicity of conventional drugs using human cell substrates, and development of experimental research tools. CSC is a privately held Delaware Corporation with headquarters and research facilities in Irvine, CA.

CSC can economically supply large quantities of high purity cells for our own clinical development pipeline in specific application areas. CSC can also supply high purity, fully characterized, clinically relevant human cell populations to companies or other institutions for development of therapies, efficacy screening or creation of toxicity profiles for candidate drugs, or experimental research.

To learn more about California Stem Cell please visit: www.californiastemcell.com
Find us on Facebook: www.facebook.com/csc
Follow us on Twitter: http://twitter.com/castemcell

# # #

For the original version on PRWeb visit: www.prweb.com/releases/prweb2011/5/prweb8390942.htm

University of Michigan develops 2 lines of embryonic stem cells to study diseases

2011-04-05T09:42:00.000-05:00

In a development that aims to provide better answers for the treatment of inherited conditions, the University of Michigan announced Monday that it has created some of the nation's first embryonic stem cell lines that carry genes responsible for specific diseases.

U-M's discovery involved the creation of two cell lines for hemophilia B, a blood-clotting disorder, and Charcot-Marie-Tooth disease, a neurological disorder that causes weakness in the legs, hands and feet.

"This will fuel the fire of discovery" in how the earliest embryonic cells develop markers of a specific disease, said Dr. Gary Smith, co-director of U-M's Consortium for Stem Cell Therapies and leader of the university's cell-derivation project.

Of nearly 100 embryonic stem cell lines in a national registry, only Harvard and Stanford universities have developed reproducible lines to study specific diseases.

U-M expects to develop cell lines to study other disorders, including Huntington's disease, myotonic dystrophy, Rett syndrome, spinal muscular atrophy and Tay-Sachs disease.

In 2008, Michigan voters approved the use of embryos discarded in fertility procedures for stem cell research. The work remains controversial. Right-to-life organizations oppose embryonic research, saying it is destruction of human life.

The cell lines will be submitted in the next few months to the National Institutes of Health. They will be stored in a national embryonic stem cell line registry.

The lines were developed through a collaboration with fertility specialist Dr. Mark Hughes, whose Detroit company, Genesis Genetics, provided U-M with embryos that tested positive for the diseases. The company specializes in pre-implantation genetic diagnosis, a technique that can detect disease from a single cell in an eight-celled embryo.

Samples from the two new cell lines will be distributed to researchers at U-M and collaborating institutions statewide, U-M said.

Contact Patricia Anstett: 313-222-5021 or panstett@freepress.com

Assessing spinal muscular atrophy with quantitative ultrasound

2011-03-18T08:23:00.000-05:00

Assessing spinal muscular atrophy with quantitative ultrasound
Sigrid Pillen, Nens van Alfen, Eric J. Sorenson, Andrea J. Boon, Jim
S. Wu, Basil T. Darras, and Seward B. Rutkove
Neurology. 2011; 76(10): p. 933-934
http://www.neurology.org/cgi/content/full/76/10/933?ct
(Unfortunately, I don't have access to the organization.)

Enzo Biochem Unit Launches First-to-Market Survival Motor Neuron (SMN) Protein Immunoassay System

2011-03-15T10:34:00.000-05:00

Enzo Biochem Unit Launches First-to-Market Survival Motor Neuron (SMN) Protein Immunoassay System

Business Wire

03/15/11 - 07:30 AM EDT

Enzo Biochem, Inc. and the Spinal Muscular Atrophy (SMA) Foundation today announced that Enzo’s wholly owned subsidiary, Enzo Life Sciences Inc., has launched a unique immunoassay (ELISA) system which can be used for the identification and detection of Survival Motor Neuron (SMN) protein. The kit is the result of a collaborative agreement between Enzo and the SMA Foundation for the development of reagents and assays for SMN protein. The availability of an effective SMN ELISA could further enable and expedite drug discovery, development and therapy for Spinal Muscular Atrophy, the leading genetic cause of mortality in infants and toddlers.

SMA is a genetic, neuromuscular disease caused by progressive degeneration of nerve cells in the spinal cord that leads to muscular weakness and atrophy and increased risk for early death due to respiratory failure. It is estimated that SMA affects approximately 1 in 6,000 to 1 in 10,000 live births worldwide. The disease is linked to a mutation in or deletion of the SMN1 gene, resulting in reduced levels of SMN protein. An active area of therapeutics development has been elevation of SMN protein levels.

“The SMN ELISA kit addresses a critical gap in SMA research and is expected to significantly accelerate SMA therapeutics development. Development and distribution of this system could not happen without the successful collaboration with Enzo and contributions from the SMA research community,” said Karen Chen, Ph.D., the Chief Scientific Officer of the SMA Foundation.

The Enzo SMN ELISA Kit provides a reliable and widely-accessible means for researchers to measure SMN protein levels, and greatly simplifies and accelerates efficacy assessment of potential drugs in clinical trials that are designed to increase SMN protein levels. The assay has been validated for use with human and mouse cell lysates and tissue homogenates, such as peripheral blood mononuclear cell (PBMC) lysates, and will be marketed through Enzo’s worldwide sales and marketing group.

“During the assay development, the SMA Foundation facilitated the supply of assay kits to affiliated researchers in the US and abroad. This allowed us to validate the assay in-house while simultaneously receiving valuable feedback about assay specifications, performance, and protocols from scientists who will ultimately be using the kits in their studies,” said Wayne Patton Ph.D., Chief Scientific Officer at Enzo Life Sciences. “Our custom assay development team continues to work with the SMA Foundation to expand the utility of the kit to include additional sample types and protocols relevant to SMA research programs and model systems, which should add further value to the assay in the marketplace.”

About Enzo Biochem

Enzo Biochem, Inc., is a growth-oriented integrated life sciences and biotechnology company focused on harnessing biological process to develop research tools, diagnostics and therapeutics, and serves as a provider of test services, including exotic tests, to the medical community. Since our founding in 1976, our strategic focus has been on the development of enabling technologies in the life sciences field. Enzo Life Sciences develops, produces and markets proprietary labeling and detection products for gene sequencing, genetic analysis and immunological research, among others. Its catalog of over 30,000 products serves the molecular biology, drug discovery and pathology research markets worldwide. Enzo Clinical Labs provides laboratory services for a growing roster of physicians in the New York Metropolitan area, Pennsylvania and New Jersey. Its tests include, in addition to routine tests, capabilities for detecting molecular infection disease, molecular oncology, autoimmune disorders and genetics. Enzo Clinical Labs also provides clinical diagnostic services that allow Enzo to capitalize on its extensive advanced molecular and cytogenetic capabilities and the broader trends in predictive and personalized diagnostics. Enzo Therapeutics is a biopharmaceutical venture that has developed multiple novel approaches in the areas of gastrointestinal, infectious, ophthalmic and metabolic diseases. It has focused its efforts on developing treatment regimens for diseases and conditions for which current treatment options are ineffective, costly, and/or cause unwanted side effects. In the course of the company’s research and development activities, Enzo has also developed a substantial portfolio of intellectual property asset with patent coverage across a number of key technologies.

Except for historical information, the matters discussed in this news release may be considered "forward-looking" statements within the meaning of Section 27A of the Securities Act of 1933, as amended and Section 21E of the Securities Exchange Act of 1934, as amended. Such statements include declarations regarding the intent, belief or current expectations of the Company and its management, including those related to cash flow, gross margins, revenues, and expenses are dependent on a number of factors outside of the control of the company including, inter alia, the markets for the Company’s products and services, costs of goods and services, other expenses, government regulations, litigations, and general business conditions. See Risk Factors in the Company’s Form 10-K for the fiscal year ended July 31, 2010. Investors are cautioned that any such forward-looking statements are not guarantees of future performance and involve a number of risks and uncertainties that could materially affect actual results. The Company disclaims any obligations to update any forward-looking statement as a result of developments occurring after the date of this press release.

About the SMA Foundation

Founded in 2003, the Spinal Muscular Atrophy Foundation is a nonprofit organization dedicated to accelerating progress towards a treatment and cure for Spinal Muscular Atrophy through targeted funding of clinical research and novel drug development efforts. Since its inception, the Foundation has awarded over $75 million for SMA research. In addition, the Foundation is committed to raising awareness and generating support for increased research efforts in SMA among the leaders of industry and government.

For more information on the Spinal Muscular Atrophy Foundation, please visit www.smafoundation.org.

Proteomic assessment of a cell model of spinal muscular atrophy

2011-03-09T09:35:00.000-06:00

Proteomic assessment of a cell model of spinal muscular atrophy

Deletion or mutation(s) of the survival motor neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), a neuromuscular disease characterized by spinal motor neuron death and muscle paralysis. Complete loss of the SMN protein is embryonically lethal, yet reduced levels of this protein result in selective death of motor neurons.

Why motor neurons are specifically targeted by SMN deficiency remains to be determined. In this study, embryonic stem (ES) cells derived from a severe SMA mouse model were differentiated into motor neurons in vitro by addition of retinoic acid and sonic hedgehog agonist.

Proteomic and western blot analyses were used to probe protein expression alterations in this cell-culture model of SMA that could be relevant to the disease.

Results: When ES cells were primed with Noggin/fibroblast growth factors (bFGF and FGF-8) in a more robust neural differentiation medium for 2 days before differentiation induction, the efficiency of in vitro motor neuron differentiation was improved from ~25% to ~50%. The differentiated ES cells expressed a pan-neuronal marker (neurofilament) and motor neuron markers (Hb9, Islet-1, and ChAT).

Even though SMN-deficient ES cells had marked reduced levels of SMN (~20% of that in control ES cells), the morphology and differentiation efficiency for these cells are comparable to those for control samples. However, proteomics in conjunction with western blot analyses revealed 6 down-regulated and 14 up-regulated proteins with most of them involved in energy metabolism, cell stress-response, protein degradation, and cytoskeleton stability.

Some of these activated cellular pathways showed specificity for either undifferentiated or differentiated cells. Increased p21 protein expression indicated that SMA ES cells were responding to cellular stress.

Up-regulation of p21 was confirmed in spinal cord tissues from the same SMA mouse model from which the ES cells were derived.

Conclusion: SMN-deficient ES cells provide a cell-culture model for SMA. SMN deficiency activates cellular stress pathways, causing a dysregulation of energy metabolism, protein degradation, and cytoskeleton stability.

Author: Chia-Yen WuDosh WhyeLisa GlazewskiLeila ChoeDouglas KerrKelvin LeeRobert MasonWenlan Wang

Credits/Source: BMC Neuroscience 2011, 12:25

Stem cell study could aid motor neurone disease research

2011-03-01T12:01:00.000-06:00

Thanks for the post Tom.

Reposting

Public release date: 1-Mar-2011
[ Print | E-mail | Share ] [ Close Window ]

Contact: Tara Womersley
tara.womersley@ed.ac.uk
44-131-650-9836
University of Edinburgh

Stem cell study could aid motor neurone disease research
Scientists have discovered a new way to generate human motor nerve cells in a development that will help research into motor neurone disease
Scientists have discovered a new way to generate human motor nerve cells in a development that will help research into motor neurone disease.

A team from the Universities of Edinburgh, Cambridge and Cardiff has created a range of motor neurons – nerves cells that send messages from the brain and spine to other parts of the body – from human embryonic stem cells in the laboratory.

It is the first time that researchers have been able to generate a variety of human motor neurons, which differ in their make-up and display properties depending on where they are located in the spinal cord.

The research, published in the journal Nature Communications, could help scientists better understand motor neurone disease. The process will enable scientists to create different types of motor neurons and study why some are more vulnerable to disease than others.

Motor neurons control muscle activity such as speaking, walking, swallowing and breathing. However, in motor neurone disease – a progressive and ultimately fatal disorder – these cells break down leading to paralysis, difficulty speaking, breathing and swallowing.

Previously scientists had only been able to generate one particular kind of motor neuron, which they did by using retinoic acid, a vitamin A derivative.

In the latest study, scientists have found a way to generate a wider range of motor neurons using a new process without retinoic acid.

Professor Siddharthan Chandran, Director of the Euan MacDonald Centre for Motor Neurone Disease Research at the University of Edinburgh, said: "Motor neurons differ in their make-up, so understanding why some are more vulnerable than others to disease is important for developing treatment for this devastating condition."

Dr Rickie Patani, of the University of Cambridge, said: "Although motor neurons are often considered as a single group, they represent a diverse collection of neuronal subtypes. The ability to create a range of different motor neurons is a key step in understanding the basis of selective subtype vulnerability in conditions such as motor neuron disease and spinal muscular atrophy."

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Genzyme Scientists Publish a Review Article Summarizing Current Data on Gene Therapy for Spinal Muscular Atrophy

2011-02-23T09:31:00.000-06:00

Genzyme Scientists Publish a Review Article Summarizing Current Data on Gene Therapy for Spinal Muscular Atrophy

February 22, 2011

Dr. Passini and Dr. Seng at Genzyme Corporation publish an article in the Journal of Trends in Molecular Medicine reviewing the current status of Gene Therapy for Spinal Muscular Atrophy. Below are two excerpts taken from the article, including the paper abstract and the concluding remarks.

Abstract:

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of functional SMN protein because of mutations in SMN1. A decrease in SMN activity results in motor neuron cell loss in the spinal cord, leading to a weakness of the proximal muscles responsible for crawling, walking, head/neck control and swallowing as well as the involuntary muscles that control breathing and coughing. Thus, patients present with pulmonary manifestations, paralysis and a shortened lifespan. Gene therapy is emerging as a promising therapeutic strategy for SMA given that the molecular basis for this monogenic disorder is well established. Recent advances and findings from preclinical studies in animal models provide optimism that gene therapy might be an effective therapeutic strategy for treating SMA.

Concluding remarks:

In conclusion, AAV-mediated SMN gene augmentation is highly efficacious at treating both the muscle and nerve aberrations of SMA mice. Viral dose, SMN expression levels and motor neuron transduction efficiency were all shown to influence the degree of efficacy in SMA mice. The CNS-targeted delivery of AAV vectors encoding SMN improved the median survival of SMA mice by 880% and the intravascular delivery of similar vectors provided for a complete rescue in survival. These improvements in longevity are remarkable given the severity of the disease phenotype in the SMA mouse model; indeed, a 25–50% increase in median survival has historically been considered a ‘successful’ outcome.

Clearly, the robust therapeutic efficacy of gene therapy makes this modality a potential clinical development candidate for SMA. Identifying the proper SMA patient population to enter clinical trials is also a topic of debate. Highly affected type 1 patients provide the highest reward-to-risk benefit, but it is not known if there are enough motor neurons remaining at the time of intervention for clinical efficacy. Thus, if type 1 patients are recruited into trials, it will be of utmost importance that intervention is performed as early as possible to maximize the probability of observing a beneficial therapeutic outcome. Types 2 and 3 patients are vastly fitter than type 1 subjects are, but they exhibit a slower disease progression that might require a trial design of several years to produce measurable improvements. What is agreed on, however, is that the heterogeneity of disease severity underscores the importance of designing and conducting separate trials for each of the SMA subtypes. Regardless of the patient population to be targeted, widespread motor neuron transduction with a minimally invasive delivery strategy must be demonstrated in large animal models if gene therapy is to be considered a competitive platform for the clinic. This final piece of the puzzle will ultimately determine the path forward and clinical utility of this therapeutic modality for SMA.

Study with Funding from FSMA Shows a Muscle Specific Intervention Improves Phenotype in a Mouse Model of Spinal Muscular Atrophy

2011-02-20T17:46:00.002-06:00

Study with Funding from FSMA Shows a Muscle Specific Intervention Improves Phenotype in a Mouse Model of Spinal Muscular Atrophy.
February 18, 2011.

Dr. Charlotte Sumner and colleagues at Johns Hopkins University publish a study in the journal Human Molecular Genetics showing improvement in survival but not motor function in a severe model of Spinal Muscular Atrophy by increasing the levels of the muscle modulator Insulin-like growth factor 1 (IGF-1).

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation, and generates myocyte hypertrophy in vitro and in vivo.

The authors hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared to mIGF-1 negative SMA littermates (median survival = 14 vs. 10 days respectively, log rank p=0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Co-treatment with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior.

The authors suggest that these results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients.

Cells snag top modelling job

2011-01-17T22:11:00.000-06:00

Cells snag top modelling job
Heart disorder joins growing list of conditions getting the 'disease in a dish' treatment.

Ewen Callaway

Induced pluripotent stem cells from a long QT patient provide a useful model of the disease.Ref. 1
When an unconscious 28-year-old woman with a rare heart disorder was rushed to hospital, surgeons saved her life by implanting a defibrillator. In time, a sample of her cells, alive and beating in a dish, could help to save other lives.

This is the hope for patient-specific models of disease, which can be created by reprogramming the patient's cells in the lab into an undifferentiated stem-cell state and then converting them into the specialized cell types affected by the condition. A handful of such models have been created so far for diseases ranging from diabetes to rare neurodegenerative diseases (see Table 1), with many more expected soon. Pharmaceutical companies are beginning to use these cells to identify effective drug treatments and to predict side effects that may only appear in a small subset of patients.

"The patient's cells act exactly as the patient was acting when admitted to the hospital," says Lior Gepstein, a stem-cell biologist at the Technion Israel Institute of Technology in Haifa, Israel. His team created induced pluripotent stem (iPS) cells from skin cells donated by the young woman, who suffers from a genetic form of long QT syndrome. They then reprogrammed the cells into heart-muscle cells called myocardiocytes, which can be used to study the disease. Their work was published in Nature1 on 16 January.

Long QT syndrome — which gets its name from a telltale anomaly in a patient's electrocardiogram — is caused by delayed electrical recharging in heart-muscle cells. The condition typically stems from inherited mutations in molecular channels that pump ions in and out of cells. People with long QT often die suddenly from arrhythmias, a kind of irregular heartbeat, in their 20s and 30s. No good animal models of the condition exist, says Gepstein, because rodent hearts beat many times faster than the human heart and use different ion channels.

Heart-muscle cells created from the patient's iPS cells, however, recreated several aspects of her disease in a Petri dish. The cells didn't recharge as quickly as heart-muscle cells made from 'healthy' iPS cells, for example. An earlier patient-specific model of a different form of long QT syndrome found similar results2. Both the 'healthy' and the long QT patient-derived heart-muscle cells formed cell sheets in the Petri dish that developed a rudimentary 'heart beat'. But the patient's cells pulsed irregularly (see video). "The normal cells of a healthy individual went boom–boom–boom; of the long QT patient they went boom–boom–boomboomboomboom," Gepstein says, doubling his tempo.

Three medicines that help heart cells recharge by targeting different kinds of ion channels all prevented arrhythmias in the diseased cells, proving the model's potential for drug screening. Moreover, the long QT patient's cells beat more irregularly when Gepstein's team treated them with a gastric-acting drug, cisapride, which was pulled from the market in 2000 because it caused lethal arrhythmia in some patients.

Predicting such side effects may be the first application for cells from long QT patients, says Gepstein. But he thinks that the eventual goal of patient-specific disease models should be personalized medicine. Clive Svendsen, director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, agrees: "You could prescribe the best drug for a patient without rotating through different drugs and without the danger of multiple side effects."

Christine Mummery, a stem-cell biologist at the University of Leiden in the Netherlands, disagrees, saying that making personalized disease cells is too time-consuming and expensive to treat individual patients. But testing drugs against disease cells from numerous patients and comparing the cells' genetics with their responses could reveal markers that could guide treatment more generally, she says.

First, though, scientists need to overcome a shortcoming of the disease-in-the dish strategy: many patient-specific iPS cell lines don't show any obvious defects related to a disease after conversion into the relevant cell types. Gepstein's team chose long QT syndrome because it stems from genetic mutations that lead to an obvious change in the heart cells. Other conditions successfully modelled from a patient's cells, such as spinal muscular atrophy and Fanconi anaemia, also come with obvious genetic causes and clear physiological readouts. "These are all low-hanging fruits," says Mummery.

Mike Venuti, president of biotech company iPierian in San Francisco, California, says that complex diseases could be modelled if the condition has a distinct effect on cells that is not present in healthy comparisons. For instance, insulin-secretion defects in patient-specific pancreatic β cells could be a proxy for diabetes. His firm has made iPS cells from people with Alzheimer's disease, Parkinson's disease and type 2 diabetes and converted them into various cell types for drug screening. He expects that drugs identified using this method will reach clinical trial for conditions such as spinal muscular atrophy in the next few years.

For all the enthusiasm about disease models made from iPS cells, embryonic stem cells (ES cells) shouldn't be forgotten for drug screens, says Stephen Minger, at GE Healthcare in Cardiff, UK. His firm is developing drug-safety tests — including for heart arrhythmias — using ES cells. He adds that the genetic manipulations used to make iPS cells could harm them and cloud the search for disease traits. "I think the field has gone a little bit overboard on iPS cells. I think they have tremendous potential, but ES cells do as well."

Happy New Year!

2011-01-01T18:13:00.000-06:00

I started this blog just to capture research news on SMA in hopes that some day a researcher would find it helpful to have an easy resource to refer to when looking for past work in this space.
It now has over 30 subscribers which is kind of scary but also encouraging given the fact that I have not advertised at all.

Best wishes to all the reader for 2011. I hope we find a cure for SMA soon.

Warm regards,
Edmund Lee

4th Annual Garage Sale for a Cure Raises Over $18,500 for Families of SMA

2010-12-17T17:04:00.000-06:00

Angie is my daughter :)

4th Annual Garage Sale for a Cure Raises Over $18,500 for Families of SMA
Published on December 17, 2010 by Families of SMA in Family Stories0 Comments
“Kyra’s Idea, Angie’s Hope” Surpasses Fundraising Goals

About four years ago, Kyra Scadden began collecting pennies in an effort to raise money to help find a cure for her friend Angie Lee’s disease, Spinal Muscular Atrophy. In 2006, the fundraising efforts turned into an annual Garage Sale event, drawing thousands of dollars. This year’s Garage Sale for a Cure was held in Naperville, Illinois, on September 25th, 2010. The goal for this year was $14,000, and they were able to surpass that goal by raising over $18,500!

Most second-graders would be intimated by a girl in a wheelchair, but when they met, Angie made Kyra feel comfortable enough to approach her and explain her disease. The girls’ friendship also quickly led to another between their moms, Kris Scadden and Kim Lee. The girls are now in middle school, but their friendship is stronger than ever. A large group of kids went to the Hilltopper dance recently at Hill Middle School, and they all wore the fundraiser T-shirt that reads, “Kyra’s Idea, Angie’s Hope”. They all danced as a group with Angie in the middle.

Kris and Kim began conversations regarding this year’s Garage Sale back in February. Kim says that her favorite part of the sale is not the money raised but the encouragement they are able to provide to other families with children who have SMA. Many of those families now come to the garage sale to see how Angie is thriving, and gain personal hope for their own children.

Kris and Kim are tearful with tears of happiness and appreciation for all the support they have received to make the garage sale successful. One neighbor, Martha Baker, provided the connection for an amazing rock concert right on Ambleside Circle in Naperville. Mr. Nicky is a music artist for kids who volunteered his time and talent. Tickets for his concert were sold for $10 per family and included a CD. Mr. Nicky writes educational parodies to popular music, and he personally wrote two songs for the garage sale.

Another area of support came from a non-profit organization called ADK Charities, which helps other non-profit organizations. About two years ago Kris met a gentleman on plane that runs ADK Charities. They selected the Garage Sale and held their own fundraiser to raise money for the event. They have also helped enormously by providing guidance and support including how to write press releases, etc.

Their organization likes to make direct contributions to research as well and asked who they could fund. Dr. Burghes at OSU (who sits on the FSMA medical advisory board) was recommended to them, and as a result, Dr. Burghes received $3,000 from them to help with SMA research.

To see more photos from the event, click here. To read more about this annual event, visit www.angieshope.org.

Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy

2010-12-17T09:49:00.000-06:00

Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy
T.-H. Chen, MD*, J.-G. Chang, MD*, Y.-H. Yang, PhD, H.-H. Mai, RN, W.-C. Liang, MD, Y.-C. Wu, BS, H.-Y. Wang, PhD, Y.-B. Huang, PhD, S.-M. Wu, PhD, Y.-C. Chen, PhD, S.-N. Yang, MD, PhD and Y.-J. Jong, MD, DMSci
+ Author Affiliations

From the Department of Pediatrics (T.-H.C., H.-H.M., W.-C.L., S.-N.Y., Y-J.J.), Division of Pediatric Emergency, Department of Emergency (T.-H.C.), and Department of Laboratory Medicine (J.-G.C., Y.-J.J.), Kaohsiung Medical University Hospital, Kaohsiung; and Graduate Institute of Medicine (T-H.C., Y.-C.C., S.-N.Y, Y-J.J.) and Institute of Clinical Medicine (J-G.C.), College of Medicine, Department of Oral Hygiene (Y.-H.Y.), College of Dental Medicine, Department of Physical Therapy (Y.-C.W., H.-Y.W.), College of Health Science, and Graduate Institute of Clinical Pharmacy (Y.-B.H.) and School of Pharmacy (S.-M.W.), College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
Address correspondence and reprint requests to Dr. Yuh-Jyh Jong, Department of Pediatrics, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Kaohsiung 80708, Taiwan yjjong@kmu.edu.tw
Abstract

Objective: The purpose of this study was to evaluate the safety and efficacy of hydroxyurea (HU) in spinal muscular atrophy (SMA) in a randomized, double-blind, placebo-controlled trial.

Methods: Twenty-eight patients with type 2 SMA and 29 patients with type 3 SMA were randomly assigned (2:1) to receive HU or matching placebo for 18 months. HU was initiated at 10 mg/kg/day with an 8-week titration to 20 mg/kg/day. Subjects were assessed at baseline (T0) and monthly for the first 2 months (T1–T2) and then every 2 months throughout treatment (T3–T10) and posttreatment periods (T11–T13). The primary outcome measures were the Gross Motor Function Measure (GMFM), Manual Muscle Test (MMT), and serum full-length survivor motor neuron (flSMN) mRNA. The secondary outcome measures were Modified Hammersmith Functional Motor Scale and forced vital capacity (FVC).

Results: Fifty-five patients completed this trial, which lasted from March 2007 to June 2009. Except for neutropenia, we found no differences in adverse events between the 2 groups. Compared with the placebo group, the HU group had −1.88 for GMFM (p = 0.11), −0.55 for MMT (p = 0.49), and 2.17 for flSMN mRNA (p = 0.13). Similarly, we found no difference in mean improvement of the secondary endpoints. Both groups had a trend toward a decline in FVC with little change in strength and motor function.

Conclusion: Under the current regimen and schedule, HU brought about no improvement in patients with type 2 and 3 SMA, and its main side effect was neutropenia.

Classification of evidence: This trial provides Class I evidence that HU 20 mg/kg/day does not effectively treat SMA.

Repligen awarded $1.4M for spinal muscular atrophy research

2010-12-15T08:42:00.002-06:00

Repligen Corp. has taken in $1.4 million in Muscular Dystrophy Association (MDA) funding to aid research in a treatment for Spinal Muscular Atrophy (SMA).

Repligen indicated in a press release today that it plans to use the research grant to help bring its SMA treatment, called RG3039, to human clinical trials in 2011. The funding also brings the Waltham biotech access to MDA’s researchers, doctors, patients and development programs.

RG3039 is an inhibitor of an RNA processing enzyme that targets higher production levels of a protein found in insufficient levels in SMA patients.

SMA is a genetic neurodegenerative disease that leads to motor neuron damage, muscle function loss and, often, death at an early age.

Repligen (Nasdaq: RGEN) has amassed a number of grants from the Muscular Dystrophy Association, mainly related development of treatments for Friedreich’s ataxia, including a December 2009 grant of $731,000 and a September 2008 grant of just over $1 million.

California Stem Cell Inc. Files IND to Commence Phase I Clinical Trial in Spinal Muscular Atrophy

2010-12-02T11:23:00.002-06:00

December 01, 2010 09:29 AM Eastern Time
California Stem Cell Inc. Files IND to Commence Phase I Clinical Trial in Spinal Muscular Atrophy

IRVINE, Calif.--(BUSINESS WIRE)--California Stem Cell, Inc. (CSC) and Families of Spinal Muscular Atrophy (FSMA) announced today that CSC has filed an investigational new drug (IND) application with the US Food and Drug Administration (FDA) for approval to commence a Phase I safety study on a jointly-developed stem cell-derived motor neuron transplantation therapy for Spinal Muscular Atrophy (SMA) Type I.

SMA is the leading genetic cause of death of infants. It is a disorder that results from a chronic deficiency in the production of the SMN protein, which is essential to the proper functioning of the motor neurons in the spinal cord. SMA is typically marked by the deterioration of the muscles that control crawling, walking, swallowing and breathing. Approximately 1 in every 6000 babies born is affected. 1 in 40 people, or approximately 7.5 million people in the US, are genetic carriers. SMA Type I, the most severe form of the disease, progresses very rapidly and is often fatal in the affected infants. To date, there are no treatments for this disease.

CSC, a leading stem cell therapeutics company, has developed a stem cell-derived motor neuron transplantation therapy, MotorGraft™, for the treatment of SMA Type I. Pre-clinical studies completed in collaboration with the Hans Keirstead Research Group at the University of California, Irvine have shown functional benefit and safety in animal models. CSC’s MotorGraft™ was granted orphan drug status for treatment of SMA by the FDA in late 2009.

Filing of this application is the first step in a multi-phase clinical development pathway aimed ultimately at approval of a novel therapy. The approval process for cutting-edge therapeutic approaches such as cell products may present unique regulatory challenges compared to conventional drugs, so companies and the FDA must work in close partnership to ensure safety and efficacy of these first in-human products. A cautious regulatory approach has been the norm in cell therapy applications submitted to date in other disease areas.

The trial will study the safety of MotorGraft™ and the surgical procedure required to deliver these cells directly into the spinal cords of patients with SMA Type I and will enroll a very limited number of patients. This IND filing is a major milestone in the search for a treatment for SMA patients.

About Families of Spinal Muscular Atrophy

Families of Spinal Muscular Atrophy is dedicated to creating a treatment and cure by: Funding and advancing a comprehensive research program; Supporting SMA families through networking, information and services; Improving care for all SMA patients; Educating health professionals and the public about SMA; Enlisting government support for SMA; Embracing all touched by SMA in a caring community. FSMA’s vision is a world where Spinal Muscular Atrophy is treatable and curable.

Families of SMA is a non-profit 501(c)3 tax exempt organization with 30 Chapters throughout the United States and over 70,000 members and supporters. Families of SMA funds and directs the leading SMA research programs. The successful results and progress from basic research to drug discovery programs to clinical trials provide real hope for families and patients.

Web site: http://www.curesma.org

About California Stem Cell, Inc.:

California Stem Cell, Inc. is a privately held company focused on the manufacture of high-purity human cells for therapeutic development and screening applications. Since its founding in 2005, CSC has developed and has intellectual property surrounding methods for scalable production of human motor neurons, neuronal progenitors, cardiac cells and liver cells at its Irvine, California facility. CSC is currently developing stem cell-derived therapies for spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal cord injury.

SMA Drug Pipeline 2010

2010-11-19T12:16:00.000-06:00

Click link to download.

Families of Spinal Muscular Atrophy Launches Next Phase of Drug Development Efforts for SMA.

2010-11-11T11:10:00.002-06:00

Families of Spinal Muscular Atrophy Launches Next Phase of Drug Development Efforts for SMA.
November 11, 2010.

Families of SMA announces Request for Proposals (RFP) for new drug programs to develop therapies for Spinal Muscular Atrophy.
FSMA has made significant progress in advancing new therapies for SMA, starting with funding the first ever SMA drug program in 2000. The organization is now launching the next phase of therapeutic development work for SMA. FSMA is aiming to fund two new preclinical drug development programs in 2011, with more to follow. These multi-million dollar collaborations will focus on innovative methods of developing novel therapies for SMA, including both biologic and small molecule approaches. These programs will be multi-year in scope with a typical duration of three years. The requested proposals will be reviewed by the FSMA Translational Advisory Committee next spring.

Families of SMA has been investing in and advancing pre-clinical drug research since 2000, with a total investment of $17 million in this area. Over the last decade, our community has made great strides in this area, and currently there are a number of promising drug avenues for SMA emerging. This progress is also clearly demonstrated by the successful transition of several potential therapies to industry and government funding after early stage investment and research leadership by Families of SMA.
Click here to see the current drug pipeline.

Drug development is high risk with less than 10% of therapies that reach clinical trials ultimately receiving FDA approval. Our research model is based on advancing multiple opportunities at once, and then incentivizing and encouraging companies and the government to fund activities in later clinical stages. Having multiple “shots on goal” gives us the best potential for reaching our goal of a treatment and cure for SMA.

FSMA has made significant progress in the area of discovering and developing new therapies for SMA. To date we have funded and advanced five such ventures:
1. Since 2000 with an investment of $13 million, the Quinazoline Compound to increase production of the back-up SMN2 gene, which was licensed to Repligen in 2009 for clinical development and is now in preparation to file for approval to start clinical trials. This new drug candidate recently received the first ever Orphan Disease Designation from the FDA for SMA.
2. Since 2003, the Oligonucleotide Program at UMASS, which identified an important therapeutic strategy using genetic material to modify the splicing of the back-up SMN2 gene. This discovery was recently licensed to ISIS Pharmaceuticals, who now leads the clinical development program.
3. Since 2003 with an investment of $2 million, the MotorGraft Cellular Therapy Program at California Stem Cell Inc, University California, Irvine and Johns Hopkins, which completed the first ever pre-Investigational New Drug Meeting with the FDA for SMA.
4. Since 2004 with an investment of $2 million, the Tetracycline Program at Paratek Pharmaceuticals to correct SMN2 splicing, which is now being funded in part from a multi-million dollar award by the NINDS.
5. Starting in 2010, the Gene Therapy Program at Nationwide Children’s Hospital in Ohio, to replace the entire SMN1 gene.

As demonstrated by the projects described above, one of the long term goals at FSMA is to fund and de-risk early stage drug discovery programs for SMA. At the very earliest stages of drug development programs have less than a 1% chance of FDA approval. This inherent risk along with low potential for profit because of the small patient population has traditionally hindered industry from working on orphan diseases.

FSMA has actively reduced the barriers to early stage SMA drug discovery programs by providing: 1) early seed funding, 2) access to tools and reagents, 3) expert SMA advisors, and 4) established clinical trial protocols and networks.

The FSMA rational for providing these incentives to industry to work on SMA drug discovery is to build a large and diverse therapeutic pipeline. Through this new RFP, FSMA will continue its long-term commitment to investment in this area. This next phase of SMA drug development will build on our success of advancing 5 programs over the last 10 years, and rapidly create a broader SMA therapeutic pipeline.
Please click here to read the most recent research newsletter.
Please click here to read the full RFP.

The selection of the most promising projects will be governed by the FSMA Translational Advisory Committee (TAC), which is made up of experts from multiple facets of drug development. The use of TAC to select drug programs for funding fits perfectly with the overall FSMA research funding model, which is based on the need for expert and independent prioritization and oversight of research projects. This approach ensures that FSMA funds only the most promising research, and that funded projects are run in a professional and efficient manner under the guidance of world-class experts.

About Families of Spinal Muscular Atrophy:
FSMA is dedicated to creating a treatment and cure by: Funding and advancing a comprehensive research program; Supporting SMA families through networking, information and services; Improving care for all SMA patients; Educating health professionals and the public about SMA; Enlisting government support a; Embracing all touched by SMA in a caring community. www.curesma.org

Families of SMA funds and directs the leading SMA research programs. Our successful results and progress from basic research to drug discovery programs to clinical trials provides real hope for families and patients.
-Families of SMA has funded 5 multi-center clinical trials for existing drugs that have potential for SMA.
-FSMA has funded 5 leading new drug development programs for therapies specially designed to treat SMA.
FSMA is a non-profit, 501(c)3 tax exempt organization with 30 Chapters throughout the United States and over 70,000 members and supporters.

Trophos Initiates Pivotal Efficacy Study of Olesoxime in Spinal Muscular Atrophy

2010-10-18T10:04:00.000-05:00

Trophos SA has announced the initiation of the pivotal efficacy study of olesoxime in the rare, neurodegenerative condition, Spinal Muscular Atrophy (SMA). The study is substantially funded by Trophos’ partnership with the Association Française contre les Myopathies (AFM) (see release of 19 March 2009). The trial protocol has benefited from the EMA Protocol Advice procedure. Efficacy results are expected in 2013.

Spinal Muscular Atrophy is an autosomal recessive genetic disease that affects the motor neurons of the voluntary muscles that are used for activities such as crawling, walking, head and neck control, and swallowing. Approximately 1 in 6000 babies born are affected and about 1 in 40 people are genetic carriers. SMA patients are divided into four subtypes depending on disease onset and severity but all suffer from degeneration of motor neurons controlling voluntary muscles with proximal limb and trunk muscle weakness leading to respiratory distress and in the most severe cases, ultimately death.

“SMA is a debilitating neuromuscular disease and there is an immense need for a treatment that can slow down or prevent the loss of muscle function in SMA patients, for whom no specific treatment exists today," said Christian Cottet, managing director of the AFM. “The AFM has been working with Trophos since 2001 and the initiation of this clinical study with olesoxime in SMA is the fruit of our long standing partnership. Thanks to the donations to the French Telethon, the AFM is supporting 36 clinical trials involving 30 different diseases. These trials accelerate the development of the therapies of tomorrow: gene therapy, stem cells, pharmacogenomics - for rare diseases and common diseases.”

Olesoxime (TRO19622) is the lead compound of the Trophos' proprietary cholesterol-oxime compound family of mitochondrial pore modulators. Preclinical studies have demonstrated that olesoxime promotes the function and survival of neurons and other cell types under disease-relevant stress conditions through interactions with the mitochondrial permeability transition pore (mPTP) and olesoxime has been shown to be active in the NSE-Cre F7/F7 model of SMA.

Olesoxime is currently undergoing a pivotal efficacy study in another rare motor neuron disease, Amyotrophic Lateral Sclerosis (ALS), which has recruited 512 patients and for which results are expected in Q4 2011. Olesoxime has successfully completed a phase 1b study in SMA patients, having previously completed phase I/Ib studies in healthy volunteers and ALS patients. These clinical trials demonstrated that the product is well-tolerated and has an excellent safety profile. They also showed that once-a-day oral dosing achieves the predicted exposure level required for efficacy, based on preclinical models.

“Olesoxime has a promising profile as a potential treatment for SMA and we are hopeful the results of this study will demonstrate that promise, bringing a much needed treatment option and new hope to SMA patients and their families," added Jean-Louis Abitbol, Chief Medical Officer at Trophos. “We are delighted to be working with the AFM and major clinical centers around Europe to undertake this clinical trial.”

Trial design and end-points:

The study is a 24-month randomized, parallel group, double-blind, placebo controlled trial comparing olesoxime against placebo in non-ambulant SMA patients aged from 3 years upwards. Olesoxime will be dosed at 10 mg/kg/day and patients will be randomized to receive olesoxime in a 2:1 ratio versus placebo. It is planned that around 160 patients will be recruited into the study in approximately 20 centers in France, Italy, Germany, UK, Belgium, the Netherlands and Poland.

The primary end-point of the study is the change from baseline in the MFM functional scale. Secondary endpoints include the Hammersmith functional scale and electromyography (CMAP - Compound Muscle Action Potential – and MUNE – Motor Unit Number). There will be an interim analysis for efficacy and futility after one year. Safety and tolerability will be closely monitored and an independent Data Safety Monitoring Board will oversee the trial.

The study is sponsored by Trophos and is being performed by a consortium of prominent European clinical investigators, all of whom have extensive prior experience conducting and collaborating in large multi-center clinical trials in SMA.
Further Information: http://www.trophos.com

Top 30 SMA Blogs

2010-10-13T17:02:00.003-05:00

Medical Billing

This blog is on the Top 30 list.
Check out the other blogs as well.

Edmund

Stem-cell treatment: first patient injected - Not SMA but related

2010-10-12T10:41:00.000-05:00

A newly injured patient in Atlanta, Ga., is the first to be injected with cells grown from human embryonic stem cells in a treatment developed at UC Irvine.

Geron Corp. announced Monday that the patient, at a rehabilitation hospital called the Shepherd Center, is receiving stem-cell derived neural cells. The patient, injected with the cells on Friday, will be part of phase one of the study, which seeks to assess the safety of the treatment as well as patient tolerance.

The hospital would release no identifying information about the patient, including name or sex.

"It's an historic moment," said UC Irvine stem-cell researcher Hans Keirstead, who developed the treatment along with colleague Gabriel Nistor but is not taking part in the clinical trial itself.

"It is now something that patients can sink their teeth into," he said. "This is real. It's not an idea, it's not a dream. It's real."

The treatment is for acute spinal injuries, so the patients must be within 14 days of the injury to take part. The Atlanta hospital is one of seven potential sites where the clinical trial will take place, and Geron says it will announce each site as patients are enrolled.

The company said in a release Monday that Northwestern Medicine in Chicago also is open for patient enrollment for the clinical trial.

Keirstead also is working on a stem-cell treatment for chronic, or long-term, spinal cord injuries, as well as a treatment for infants suffering from type 1 spinal muscular atrophy. He hopes the treatment for the infants, who typically die in their first years of life, will become the world's second stem-cell clinical trial.

If you live in Chicago land

2010-09-10T11:02:00.000-05:00

Please get this word out if you happen to live in Chicago land.
For more information, please visit - http://www.fsma.org/Fundraising/EventsCalendar/index.cfm?id=5421

4th Annual Garage Sale for a Cure!

Saturday, September 25^th 8am-2pm

1401 Ambleside Circle (in West Wind), Naperville IL 60540

Kyra Scadden, now a 6th grader at Hill Middle School in Naperville, is hosting her 4th annual fundraiser to raise money for a cure for Spinal Muscular Atrophy. SMA is the disease that her best friend Angie has been suffering from since she was born.

Kyra and Angie became friends in the summer of 2006 and were quickly “Best Friends”. She was very concerned about Angie's condition and also didn't like that other people didn't understand her disease. She originally decided to collect pennies to help find a cure for SMA. Within days her and her older sister, Becca, had decided to donate the proceeds of an upcoming garage sale to the cause. As the community discovered what was happening the support was overwhelming. Her goal was to raise $200 and everyone was amazed when the girls were able to raise over $9,400 in 10 days! Kyra was even more excited that people understood Angie's condition and were comfortable talking about it. When asked if she would have the sale again, Kyra said she would raise money for SMA until a cure was found. Kyra and her family are very excited about this year's event and even more excited by the amazing advances in SMA Research. With the generous support of our community Kyra has been able to send more than $30,000 to Families of SMA, an organization that funds research for a cure.

This year’s sale will be on Saturday September 25th 8-2pm. We want to invite you to this exciting garage sale fundraiser for a cure. It will be a big event that is fun for the whole family! We will have lots of great items for sale, food, drinks, silent auction, raffle and more! Bring your kids & go shopping, there is something for everyone. Meet Angie and Kyra!

If you’re unable to come to the event, there are some really great ways everyone can help:

Donate used items for the sale, provide gift cards/merchandise/services for our auction, “Shop for a cure” on our website, collecting pennies, or help us get the word out! For details, please visit www.AngiesHope.org. or contact us at kiyomy@gmail.com. You can see the YouTube video clip that girls made for the sale at http://www.youtube.com/watch?v=UDgOPmIUZfU

Thank you for continuous support for Families of SMA. I hope to see you all at the sale.

Sincerely,

Kim and Edmund Lee - Jungin Angie Lee (SMA Type 2)’s parents.

Spinal muscular atrophy research team receives Pepsi Refresh funds from Sophia's Cure Foundation

2010-09-08T10:19:00.002-05:00

Public release date: 8-Sep-2010
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Contact: Mary Ellen Peacock
MaryEllen.Peacock@NationwideChildrens.org
614-355-0495
Nationwide Children's Hospital

Spinal muscular atrophy research team receives Pepsi Refresh funds from Sophia's Cure Foundation

Nationwide Children's Hospital receives $250,000 grant for SMA research

Brian Kaspar, PhD, principal investigator in the Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital, along with a team of Spinal Muscular Atrophy (SMA) researchers and clinicians, recently received a $250,000 grant for SMA research and clinic development from Sophia's Cure Foundation via the Pepsi Refresh Project.

Spinal Muscular Atrophy (SMA) is a group of inherited debilitating neurological diseases that cause progressive muscle degeneration and weakness throughout the body. There is no treatment for the progressive weakness caused by the disease. It is estimated that SMA occurs between one-in-6,000 and one-in-20,000 births. One-in-40 to one-in-80 "normal" men and women carry the gene for SMA, and if both a man and woman carry the gene, there is a 25 percent chance that any of their children will manifest SMA.

Sophia's Cure Foundation, a not-for-profit organization created to assist in funding clinical research for SMA and to offer support to families affected by SMA by providing advocacy, awareness and education, received the $250,000 grant from the Pepsi Refresh Project and awarded it to Dr. Kaspar and his team. The Pepsi Refresh Project has committed to award more than $20 million in 2010 to projects and research that will "move communities forward." Individuals can apply for these grants to benefit a variety of projects while web site visitors vote for the best ideas.

"We are extremely honored to be able to fund such an incredibly promising program," said Vincent Gaynor of Sophia's Cure Foundation. "Dr. Kaspar and his team are some of the most talented and devoted researchers in the field. It was our mission to educate the community on their promising work, and to bring together a united effort to see Dr. Kaspar's SMA research funded. There is a tremendous amount of work yet to be done, and we look forward to continuing our support of this research."

"The Pepsi Refresh Project is an innovative funding mechanism that is clearly making a major impact for community projects," said Dr. Kaspar, also a faculty member at The Ohio State University College of Medicine. "Spinal Muscular Atrophy research and therapeutic development stands to gain from this important and generous investment, and we all look forward to translating our research to advance human clinical trials."

Both Dr. Kaspar's team and Sophia's Cure Foundation are extremely thankful for everyone that voted for their application via the Pepsi Refresh program. It is clear that the SMA community worked together and united for a common goal to push this research and cause to first place.

"This is a major win for the SMA community," said Dr. Kaspar. "We are honored and extremely appreciative for the support from both of these organizations."

The grant of $250,000 will assist Dr. Kaspar and his team at Nationwide Children's in research and development, moving their gene therapy work toward scaleable production and purification methods to perform the pivotal safety studies and produce clinical grade material as they advance this program to the clinic.

Through his SMA research, Dr. Kaspar has worked closely with, and will continue to collaborate with a host of doctors and researchers in the field, all with the common goal to find a treatment for SMA.

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