Duchenne Muscular Dystrophy: on a rational road to the cure?

Duchenne Muscular Dystrophy (DMD) is a devastating inherited muscular disorder with no cure, affecting 1 in 3,500 boys in early childhood. It is caused by mutations in the dystrophin gene coding for a cytoskeletal protein present in skeletal, cardiac and smooth muscle. The disorder progresses rapidly, resulting in a weakening of all voluntary muscles as well as the heart and breathing muscles. Prognosis is poor beyond the age of 25. Treatment is limited to supportive care to maximize quality of life.

Gene replacement therapy is an ideal candidate for treatment for this disease. All patients, regardless of the nature of their genetic mutation, would benefit from a healthy copy of the gene delivered to the affected tissues.

Recombinant adeno-associated viral (rAAV) vectors have proven to be efficient delivery vehicles of therapeutic genes for a number of diseases with recent clinical successes in humans with Leber’s congenital amaurosis and Hemophilia B. More than 40 clinical trials using rAAV are ongoing at the moment.

In the February 2012 issue of Molecular Therapy, Bowles et. al. give a comprehensive analysis of the results from a Phase 1 clinical trial, representing an rAAV dose escalation study for Duchenne Muscular Dystrophy in 6 pediatric patients. The group of doctors and researchers with wide range of expertise has used a novel synthetic AAV vector (AAV2.5) rationally engineered to target skeletal muscle tissue with high efficiency to deliver a miniaturized functional dystrophin gene. Rather than empirical comparisons of various viruses available in the lab or random shuffling of components from different viruses, “designer changes” based on known biology and structural considerations were made to the protein capsid of the recombinant virus. Preclinical data in mice showed high level of gene expression for a prolonged period of time and a favorable immune profile of the new vector’s architecture to potentially evade immune response in humans.

In the patients, the delivery of the therapeutic agent was well tolerated and did not cause advert effects. The mini-dystrophin gene was shown to be present in the target muscle tissue at up to >2 copies per cellular genome, but overall expression of mini-dystrophin protein was too low to provide functional improvement. An array of possible causes hampering the desirable therapeutic benefit range from pre-existing neutralizing antibodies against AAV to disease associated inflammation, silencing of the promoter, or perhaps low tropism of AAV2.5 to human muscle tissue. These questions are inherent to the transition from preclinical studies conducted in mice to the real clinical setting in human patients.

Still, the trial is a particularly important step on the road to future gene medicines. It was the very first clinical trial to utilize a laboratory custom designed novel AAV capsid to mediate gene delivery in patients, a prerequisite stepping stone to a new generation of better vectors and successful therapies.