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August 26, 2010

NIH Director's Response to Stem Cell Injunction

"Human embryonic stem cell research holds great promise for the development of treatments for people threatened by potentially curable diseases. The recent court ruling that halted the federal funding of human embryonic stem cell research could cause irreparable damage and delay potential breakthroughs to improve care for people living with serious diseases and conditions such as spinal cord injury, diabetes, or Parkinson’s disease. The injunction threatens to stop progress in one of the most encouraging areas of biomedical research, just as scientists are gaining momentum—and squander the investment we have already made. The possibility of using these cells to replace those that have been damaged by disease or injury is one of the most breathtaking advances we can envision. Human embryonic stem cells also represent a powerful new approach to the early stages of screening for new drugs, and may hold the secrets to creating entirely new, targeted clinical therapies. We must move forward—without delay—to sustain this field of research that provides so much hope for thousands of patients and their families."

Francis S. Collins, M.D., Ph.D., Director, National Institutes of Health

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August 24, 2010.

Project Cure SMA Clinical Trial Network Publishes New Results in Muscle and Nerve with Funding from Families of Spinal Muscular Atrophy.

The Project Cure SMA Clinical Trial Network publishes a paper entitled "Compound muscle action potential and motor function in children with spinal muscular atrophy" in the Journal Muscle and Nerve. 

Reliable tests to determine if a new therapy is working are needed for future clinical trials in SMA.  In this study, the authors evaluated one potential such test, a test of a nerve that moves the pinky finger. The specific nerve study is called the “maximum ulnar compound muscle action potential”, or CMAP for short. The CMAP was obtained non-invasively during two separate visits in children with SMA types II and III, ages 2-17 years old during the initial screening visits of the CARNI-VAl Trial, which was fully funded by Families of SMA. We also obtained an estimate of the children’s motor function during the same visits using the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS-Extend.  While  this measure may not be representative of the total overall strength of an individual, this paper shows that it correlates with disease severity and progression over time, is relatively easy to obtain, and is reproducible.

"CMAP is a direct measure of how strong the nerve being tested is. Nerves provide the potential to activate muscle. This paper demonstrates that CMAP is well correlated with other outcomes measuring motor function- the MHFMS and the MHFMS-Extend. The fact that these outcomes (CMAP, MHFMS and MHFMS-Extend) are related suggests that each outcome may provide valuable information about strength in types 2 and 3 SMA", says Kristin Krosschell, lead PT for Project Cure SMA.

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August 19, 2010

CARNI-VAL Clinical Trial Results for Spinal Muscular Atrophy Published from Project Cure SMA Network.

Project Cure SMA Trial Group Publishes Results from the SMA CARNI-VAL Trial Part I: Double-Blind, Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy.  The paper was published today in the online Journal PLoS ONE.  This clinical trial was fully funded by Families of SMA.

The study did not demonstrate functional improvement after a six month treatment with VPA and L-Carnitine.  Though the trial as designed failed to show that VPA is helpful for this SMA population, it did confirm the earlier FSMA-supported open label trial that the combination with L-Carnitine VPA is safe for children with SMA, with one consideration. Excessive weight gain is a problem for children with SMA as they grow older, and treatment with VPA may exacerbate that tendency. 

Project Cure SMA is a clinical trials network of seven sites located in the United States and Canada, funded fully by Families of SMA, which has included $7 million in funding to support the Project Cure SMA trials sites and associated infrastructure.   The network to date has focused on testing existing drugs and validating outcome measures for use in future clinical trials that may lead to a treatment for Spinal Muscular Atrophy.  Recently, an international expansion of these efforts has involved FSMA’s international Partners in Argentina and Germany.   One major goal for the project is having an operational clinical network with sufficient sites, as well as proven endpoints, to conduct pivotal SMA drug trials will help attract and encourage biotech and pharmaceutical companies to invest in SMA drug development.

CARNI-VAL Trial Part I is an FDA approved multicenter clinical trial designed to recruit Spinal Muscular Atrophy (SMA) affected children. Two cohorts of subjects were enrolled in this study, a non-ambulatory group of “sitters” and an ambulatory group of “walkers”.   This study presents results for the first group: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects with SMA were enrolled in 6 centers as part of Project Cure SMA clinical trial network (University of Utah, University of Wisconsin-Madison Health Sciences; Wayne State University; Ohio State Biomedical; Johns Hopkins Medical and Ste. Justine Hospital) and randomly selected 1:1 to Valproic Acid (VPA) and L-Carnitine, or placebo treatment for the first six months; all received active treatment the subsequent six months.  

The intent of this study was to evaluate the potential for benefit of this drug combination in children with SMA, and had several objectives in addition to evaluation of the drug itself.  The secondary objectives were to assess the safety of VPA / Carnitine in children with SMA and to assess the selected methods (outcome measures) used to assess drug efficacy in a multi-center setting, i.e. to evaluate the best means to study this or any other drug for SMA.

The study did not demonstrate functional improvement after a six month treatment with VPA and L-carnitine.  However, it did yield critically important insights. “The first trials of any drug in a new field of medicine are difficult”, said one of the study authors, Dr Tom Crawford, “because investigators have only their own untested ideas as to how best to construct a study. The design of any trial requires assumptions about which patients will be most responsive, the best duration of treatment, what means of assessment are most able to show improvement, and other choices.  Each is critical to a trial’s ability to demonstrate benefit of treatment. Although negative, from this trial the community has learned a lot that will make future trials much more powerful.”

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March 15, 2010

CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy.

Passini MA, Bu J, Roskelley EM, Richards AM, Sardi SP, O'Riordan CR, Klinger KW,Shihabuddin LS, Cheng SH.

Genzyme Corporation, 49 New York Avenue, Room 2410, Framingham, MA 01701, USA. marco.passini@genzyme.com

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by a deficiency of survival motor neuron (SMN) due to mutations in the SMN1 gene. In this study, an adeno-associated virus (AAV) vector expressing human SMN (AAV8-hSMN) was injected at birth into the CNS of mice modeling SMA. Western blot analysis showed that these injections resulted in widespread expression of SMN throughout the spinal cord, and this translated into robust improvement in skeletal muscle physiology, including increased myofiber size and improved neuromuscular junction architecture. Treated mice also displayed substantial improvements on behavioral tests of muscle strength, coordination, and locomotion, indicating that the neuromuscular junction was functional. Treatment with AAV8-hSMN increased the median life span of mice with SMA-like disease to 50 days compared with 15 days for untreated controls. Moreover, injecting mice with SMA-like disease with a human SMN-expressing self-complementary AAV vector - a vector that leads to earlier onset of gene expression compared with standard AAV vectors - led to improved efficacy of gene therapy, including a substantial extension in median survival to 157 days. These data indicate that CNS-directed, AAV-mediated SMN augmentation is highly efficacious in addressing both neuronal and muscular pathologies in a severe mouse model of SMA

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February 5 2010

H.R.2149 SMA Treatment Acceleration Act

There are 4 new Cosponsor in the House of Representatives.  We appreciate everyones support and continue to encourage you to enlist the support of your State Representative if they are not listed as cosponsors. Thank you.