Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness. It is the most common neuromuscular disorder in children. It is associated with abnormalities in the DMD gene, which encodes dystrophin, a protein essential for proper muscle function. This gene is one of the largest in our genome (approximately 11,000 coding base pairs). Because of its size, it is technically impossible to use the integrality of the DMD gene’s DNA sequence for gene therapy.
Researchers from the Genethon laboratory (supported by the AFM-Téléthon) and from the University of London (Royal Holloway) have collaborated to produce a microdystrophin gene – a “shortened” version of the dystrophin gene of approximately 4,000 base pairs – placed in a recombinant adeno-associated virus (rAAV) vector that can be used for gene therapy. Interestingly, the microdystrohy gene produces a functional protein. Researchers tested this treatment on 12 dogs suffering from DMD. It is of note that while DMD dogs show similar clinical symptoms as children suffering the same disease, the appearance of cardiac pathology in DMD dogs is very rare and with a late onset, therefore the impact of the treatment on the cardiac function could not be accessed.
In the study, the researchers injected the microdystrophin gene/ viral vector intravenously to reach all muscles of the dogs. They observed that dystrophin expression returned to a high level, and muscle function was significantly restored with stabilisation of the clinical symptoms observed for over 2 years following injection of the drug. Importantly, no immunosuppressive treatment was administered beforehand, and no side-effects were observed.
This preclinical canine trial shows promising results regarding the overall safety and efficacy of the microdystrophin gene. The researchers are now considering developing a clinical trial in patients. Caroline Le Guiner, the main author on this study wants to emphasize that “this innovative approach allows treatment of all patients with Duchenne muscular dystrophy, regardless of the genetic mutation responsible.”
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