Limb Girdle Myophaties

Research Pre-clinical phase Phase I or I/II  

Gamma-sarcoglycanopathy, or LGMD2C

is a rare form of limb girdle muscular dystrophy caused by mutations in the gamma-sarcoglycan gene (gSG). It is characterized by proximal and progressive muscular weakness which begins before the age of 10 on average, with a loss of ambulation occuring at puberty. Cardiomyopathy and respiratory failure may occur as the disease progresses, which can worsen the prognosis of the disease and may cause premature death.

Genethon has sponsored a phase I clinical trial for gamma-sarcoglycanopathy (LGMD2C).

Based on preclinical studies performed by Genethon in collaboration with the Harvard Gene Therapy Initiative in Boston and Dr. Lee Sweeney’s group at the University of Pennsylvania in the US, this trial, which started in November 2006, is directed by Professor Serge Herson at the Hôpital de la Pitié Salpêtrière in Paris.

This trial involves intramuscular administration of an AAV (Adeno-Associated Virus) vector carrying a copy of the normal gene. So far, nine patients have been enrolled in the trial.

Genethon’s gene transfer program for Duchenne muscular dystrophy may benefit from the results of this program.

 

Alpha-sarcoglycanopathy

is one of the limb girdle muscular dystrophies. It is caused by mutations in the gene for alpha-sarcoglycan, a transmembrane protein that forms part of a complex associated with dystrophin.  The condition is characterized by progressive and symmetrical muscle weakness of the torso and limbs. Cardiac involvement occurs in about 20% of cases and, in the most severe forms, patients lose the ability to walk by the age of 30 and life expectancy is shortened.

The proof of concept of the efficacy of gene therapy, based on the administration of an AAV (adeno-associated virus) vector carrying a normal copy of the mutated gene, was provided by Genethon using an animal model (Fougerousse et al., Journal Molecular Therapy, 15, 2007). Preclinical studies are currently underway in order to define the strategy for a future clinical trial.

 

Dysferlinopathies

are a spectrum of recessive muscular dystrophies caused by mutations in the gene for dysferlin, a transmembrane protein involved in membrane repair. The most common forms are limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy with distal weakness. The first manifests as weakness in the muscles of the shoulders (scapular girdle) and pelvis (pelvic girdle), whereas the second affects primarily the distal limbs (lower legs, feet, forearms and hands). There is currently no cure for these diseases.

The strategy being developed at Genethon involves administering an AAV (adeno-associated virus) carrying a therapeutic gene. Genethon has designed original methods allowing the transfer of this very large gene (Krahn et al., Journal Science Translational Medicine, 2, 2010, in collaboration with the team of Prof. N. Levy, INSERM UMR_2 910; Lostal et al., Journal Human Mol Genet, 19, 2010). Preclinical studies are currently underway in order to define the strategy for a future clinical trial.