Replacing Missing Genes

Duchenne muscular dystrophy (DMD) is the most common life-threatening childhood form of muscular dystrophy.  It is characterized by progressive weakness and degeneration of skeletal muscles and caused by a mutation in the dystrophin gene.  This mutation leads to an absence of the protein dystrophin, which is chiefly located in skeletal and cardiac muscles. “The consequences of this disease are debilitating and patients usually die from respiratory failure or heart failure in their early 20s,” said Dr. Mendell.

While science benefits from the fact that the disease-causing gene has been identified, this knowledge does not necessarily make DMD easier to prevent. “The dystrophin gene is the largest gene identified to date,” said Dr. Mendell. “Because it is so large it is susceptible to a high sporadic mutation rate, ensuring that the disease can never be eliminated.

The Muscle Group has focused on using viral vectors to deliver the needed dystrophin into muscle cells. “Viruses are ideal vehicles for therapeutic gene transfer,” said Dr. Mendell. “We’re able to replace the viral genetic material with our desired ‘good genes’ and then take advantage of the virus’ ability to transfer genetic material to host cells and infect entire systems.”

Years of experimentation with animal models have shown that virus-mediated gene delivery of a miniature version of the dystrophin gene could ultimately benefit muscles affected by DMD and be unlikely to harm.  However, recent Muscle Group studies suggest that the mini-dystrophin protein may trigger the immune system’s memory response and therefore eliminate the ability of a gene therapy strategy to successfully enhance dystrophin production in these patients.

Using a similar strategy, Muscle Group members performed a clinical gene therapy trial in 2009 to deliver the missing alpha-sarcoglycan gene to patients with limb girdle muscular dystrophy, a form of muscular dystrophy that disables patients by gradually weakening muscles near the hips and shoulders. This served as the first gene therapy trial in muscular dystrophy demonstrating promising findings.

Yet the success of gene replacement to treat any form of muscular dystrophy will hinge on patients’ immune response, a factor that Dr. Mendell says needs further study. “The influence of cellular immunity on the outcome of human gene therapy with rAAV vectors is not yet well defined.”

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