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Dr. Mendell currently serves as Director of the Center for Gene Therapy at The Research Institute at Nationwide Childrens Hospital and holds Professorships in Neurology, Pediatrics, Pathology, Physiology and Cell Biology at the Ohio State University.  He also directs the neuromuscular research program at Nationwide Children’s Hospital.  He has worked in the laboratory using experimental models of muscular dystrophy and at the bedside participating in clinical trials. Dr. Mendell is the first to perform gene therapy for DMD (March 2007) and also started a gene therapy study in LGMD2D (Nov 2007), demonstrating success for the first time.  His laboratory also recently demonstrated vascular delivery by rAAV of muscular dystrophy genes to the limbs of mice and non-human primates that will be moving toward clinical trials to make a difference in the lives of patients with devastating disease of muscle.



The results of a Phase I clinical trial of gene therapy for limb-girdle muscular dystrophy type 2C (a rare neuromuscular disease) have just been published in the journal Brain on January 11, 2012. The trial started in December 2006 and has been sponsored by Généthon (the not-for-profit research lab created by the French Muscular Dystrophy Association (AFM) and which is funded almost exclusively by donations from France's annual Telethon).

The trial at Pitié-Salpêtriere (AP-HP) is being led by principal investigators Professor Serge Herson (Head of the Department of Internal Medicine 1) and Professor Olivier Benveniste (Institute of Myology). The study's primary objective was to evaluate the safety of local injection of increasing doses of an adeno-associated virus (AAV) vector harboring a "healthy" copy of the gene for gamma-sarcoglycan (the defective protein in this disease). Secondary objectives included the assessment of local and systemic immune reactions and the quality of gene transfer in the injected muscles in terms of efficacy, expression and distribution.Nine non-ambulatory patients (aged from 16 to 38) were included in the trial between December 2006 and December 2009. Three increasing doses of an AAV1 vector bearing the normal gamma-sarcoglycan gene were injected into a forearm muscle. One month after the injection, a biopsy was taken from the treated zone and analyzed.The trial's results have just been published and are encouraging. Above all, the injections were well tolerated and not associated with adverse physical or biological effects. Furthermore, assays in five patients revealed the presence of RNA produced from the therapeutic gene (RNA is the intermediate genetic material between the gene and the protein). Immunohistochemical analysis of injected-muscle biopsy specimens showed γSGC expression in three out the three patients who received the highest dose. Furthermore, in one of these patients (who had received the highest dose of treatment), a western blot assay revealed that normal protein gamma-sarcoglycan was being expressed in the muscle fibers. Thanks to gene therapy, the missing gamma-sarcoglycan protein was being produced anew.

Professor Serge Herson commented that "the results of this trial exceed our expectations. In addition to confirming the treatment's lack of toxicity (the study's primary objective), we were able to make progress in other areas, such as trial logistics, immunological aspects and even the optimaldose for treating a set of muscles efficaciously. This result is especially interesting because it means that we have established the dose threshold above which the treatment becomes efficacious. That’s very rare in a Phase I trial".The physicians and researchers at Généthon, the Institute of Myology and Pitié-Salpêtriere (AP-HP) are continuing their work. They intend to set up a new trial in which an AAV8 vector will be used to treat a whole limb.



This open-label, single centre pilot study was designed to evaluate safety and tolerability of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a non steroid anti-inflammatory drug, in a cohort of adult dystrophic patients (Duchenne, Becker and Limb-Girdle Muscular Dystrophy).

Seventy-one patients were recruited: 35, treated with the drug combination for 12 months, and 36 untreated. Safety and adverse events were assessed by reported signs and symptoms, physical examinations, blood tests, cardiac and respiratory function tests. Exploratory outcomes measure, such as the motor function measure scale, were also applied. Good safety and tolerability profiles of the long-term co-administration of the drugs were demonstrated. Few and transient side effects (i.e. headache and low blood pressure) were reported. Additionally, exploratory outcomes measures were feasible in all the disease population studied and evidenced a trend towards amelioration that reached statistical significance in one dimension of the MFM scale. Systemic administration of ibuprofen and isosorbide dinitrate provides an adequate safety margin for clinical studies aimed at assessing efficacy.