A gene therapy being developed at Penn Medicine to treat Duchenne muscular dystrophy (DMD) successfully and safely stopped the severe muscle deterioration associated with the rare, genetic disease in both small and large animal models, according to a first-of-its-kind study from Penn Medicine researchers. The findings put the field within closer reach of a safe and effective gene therapy that uses a “substitute” protein without triggering immune responses known to hinder other therapeutic approaches.
Found mostly in boys, DMD is caused by mutations in a sex-linked gene that stop production of a muscle-building protein known as dystrophin. Without it, muscles progressively deteriorate and weaken starting at a very young age and only worsen from there. Most patients aren’t able to walk by age 12 and die of heart or respiratory failure by the time they reach their 30s, though respirators have helped some live longer.
With their modified gene therapy approach, a multidisciplinary team from the Perelman School of Medicine at the University of Pennsylvania engineered adeno-associated virus (AAV) vectors to deliver a “substitute” protein for dystrophin in small and large animal DMD models to keep the muscles intact. The synthetic substitute, based on a naturally occurring protein called utrophin, proved to be an effective and safe alternative, as it protected muscle in mice and dogs with naturally occurring DMD-like mutations, including a large deletion that closely mirrors the large dystrophin deletions found in humans.
“For the first time, we’ve shown how a carefully constructed version of a dystrophin-related protein can safely prevent the breakdown of muscle and maintain its function over time in the most informative animal models. This discovery has important implications for gene therapy and how we work toward safe and effective treatments for muscular dystrophy,” said senior author Hansell H. Stedman, MD, an associate professor of Surgery. “With these results, we have a strong rationale to move this forward into human clinical trials.”
Restoring levels of dystrophin with gene therapy and other techniques have been under scrutiny due to the immune system’s adverse reaction to additions it deems foreign. DMD patients have little to none of this protein, so their bodies can attack well-intentioned direct replacement proteins because they are seen as foreign. However, because dystrophin’s distant cousin utrophin is expressed in other places in the body, it was thought that the immune system wouldn’t view it as a threat.