A gene therapy developed by scientists at Penn Medicine for the treatment of Duchenne muscular dystrophy (DMD) was able to successfully and safely prevent the sever muscle deterioration caused by the rare, genetic disease in both small and large animal models. The study is a giant leap for the field and takes it closer to a safe and effective gene therapy that can use a ‘substitute’ protein without triggering immune responses that can obstruct other therapeutic approaches. The multidisciplinary team from the Perelman School of Medicine at the University of Pennsylvania relied on their modified gene therapy approach to engineer adeno-associated virus (AAV) vectors to give an alternative protein for dystrophin in small and large animal DMD models to keep the muscles intact.
The synthetic substitute, made from a naturally occurring protein named ‘utrophin,’ has been demonstrated as an effective and safe alternative. It has successfully protected muscle in mice and dogs that had naturally occurring DMD-like mutations, along with a large deletion that closely resembles the large dystrophin deletions observed in humans. Senior author Hansell H. Stedman, MD, Associate Professor of Surgery, says that for the first time, the team was able to show how a carefully constructed version of a dystrophin-related protein can safely prevent the breakdown muscle and maintain its functions through time in the most informative animal models. The discovery is critical for gene therapy, and these results present a strong rationale to take this forward to human trials, adds Stedman.
The team observed that when they administered a single-dose treatment of synthetic utrophin with the AAV vector to newborn mice, it led to a distribution of protein throughout the body, showed no signs of toxicity and that all signs of DMD were completely suppressed, as compared to untreated mice. The team also experimented in dogs and observed a strong expression of utrophin along with a fourfold increase in weight as well as a substantially lower level of muscle damage in the treated dogs. This is the first time that an animal study has shown utrophin’s effectiveness and its non-immunogenic response at such a scale.