Muscular dystrophies

Research Pre-clinical phase Phase I or I/II  

Limb Girdle Muscular Dystrophy 2I (LGMD2I)

is an autosomal recessive disease caused by mutations in the fukutin-related protein gene. Limb Girdle Muscular Dystrophy 2I is a heterogeneous group of conditions which manifest at ages varying between early childhood and early adulthood.

The disease is characterized by:

  • rapid deterioration and loss of ambulation during adolescence or later in adulthood
  • respiratory distress
  • heart symptoms.

There are currently no specific treatments for any of the LGMD conditions, although supportive care is essential.

In 2019, Genethon will launch a natural history trial in 4 countries (Denmark, France, UK and Germany) to learn more about the disease. This trial will recruit 60 patients and will be followed by a phase I/II gene therapy clinical trial.

 

Gamma-sarcoglycanopathy, or LGMD2C

This disease is caused by mutations in the gamma-sarcoglycan gene (gSG). It is characterized by progressive proximal muscle weakness, usually beginning before the age of 10, with a loss of ambulation occurring at puberty. Cardiomyopathy and respiratory failure may occur as the disease progresses, worsening the prognosis and causing 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 team at the University of Pennsylvania in the US, this trial, which started in November 2006, was directed by Professor Serge Herson at the Hôpital de la Pitié Salpêtrière in Paris. The trial involved intramuscular administration of an AAV (Adeno-Associated Virus) vector carrying a copy of the normal gene. Nine patients were enrolled in the trial in total.

The rest of the project will be able to benefit from the results obtained within the framework of Genethon’s gene transfer program on Duchenne muscular dystrophy.

 

Alpha-sarcoglycanopathy

This disease is caused by mutations in the gene encoding alpha-sarcoglycan, a transmembrane protein that is part of a complex associated with dystrophin. The disease is characterized by progressive and symmetrical weakness of the trunk and limb muscles. Heart involvement occurs in about 20% of cases and, in the most severe forms, patients lose the ability to walk before the age of 30 and their life expectancy is reduced.

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

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

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