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Research News and Announcements

Genzyme Scientists Publish a Review Article Summarizing Current Data on Gene Therapy for Spinal Muscular Atrophy and Ohio State University Provides a Development Update on the SMA Program.
February 25, 2011.

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.

Please click here to see the journal article.

Ohio State University and Nationwide Childrens' Hospital Provide a Development Update on the SMA Gene Therapy Drug Program with Funding From FSMA.

After the pre-pre IND meeting Dr. Brian Kaspar reports the following:

"We had our first interaction with the Food and Drug Administration regarding our gene delivery program for Spinal Muscular Atrophy on Thursday, February 24th, 2011 in what is termed a pre-pre IND (Investigational New Drug Application).  For this call, we presented pertinent information to the FDA regarding the status of our studies to date, which included pre-clinical efficacy and preliminary safety data.  We were impressed with the thorough, thoughtful and expert review we received from the agency in which the FDA was positive regarding our program, providing guidance for moving our translational program forward.  It is important to note that these discussions were informal and non-binding, but certainly provided positive direction for us to move towards human studies.  Based on our conference call and review, we are planning to perform some further dosing and safety studies that will help guide the studies that will be required for our formal application.  This was an important step in our program and we are excited to continue to advance the gene delivery program forward to the clinic."


Please click here to read more about the gene therapy for SMA.



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