Groundbreaking gene therapy offers new hope for muscular dystrophy cure

A promising new gene therapy for Duchenne muscular dystrophy (DMD) might not only halt muscle deterioration but also potentially repair damaged muscles in the future.

Researchers from UW Medicine are focusing on delivering protein packets via shuttle vectors to replace the defective DMD gene within muscle cells. This new genetic code will produce dystrophin, a protein missing in DMD patients.

Currently, there is no cure for DMD, and existing treatments only slow the disease's progression. This inherited genetic disorder, affecting only males because the gene is on the X chromosome, starts showing symptoms around age four, with most patients dying in their 20s or 30s.

The findings were published in Nature. Dr. Jeffery Chamberlain, a neurologist and geneticist at UW Medicine, is the study's senior author. He has dedicated his career to finding therapeutics and a cure for muscular dystrophy. He leads the Wellstone Muscular Dystrophy Research Center and holds the McCaw endowed chair in muscular dystrophy at the University of Washington School of Medicine. The research was led by molecular biologist Dr. Hichem Tasfaout in Chamberlain's lab.

One major challenge for researchers has been the size of the DMD gene, the largest gene in nature. Delivering adequate protein fixes into the muscles has been a significant hurdle. "Think of having a king-sized bed delivered that you can’t get through your door," Chamberlain explained.

This new method, successful in mouse models, uses adeno-associated viral vectors (AAVs). These tiny shuttles, derived from a virus, deliver gene therapies into human cells. Instead of a single AAV, this therapy uses multiple AAVs to transport parts of the therapeutic protein into the muscles, along with instructions for assembling the genetic fix once inside the body. Chamberlain likens it to taking bed parts piece by piece into a house and assembling them inside.

Human trials for this therapy are expected to start in approximately two years. In lab tests, this method has not only halted disease progression but has also reversed much of the pathology associated with dystrophy. Chamberlain and Tasfaout hope that this approach could eventually reverse muscle wasting and restore normal muscle tissue health.

This latest approach also employs a new type of AAV vector that allows for lower doses, potentially reducing or eliminating side effects associated with previous methods. "When we infuse a large dose of these delivery shuttles, the body goes 'Whoa, what’s going on here?'" Chamberlain said, noting that this immune response can damage the heart or liver.

Chamberlain recalls watching the Jerry Lewis Telethon as a child and wanting to help those children. This early interest may have sparked his passion for the field. As an expert, he has discussed the science of therapies on the telethon about seven times. "When you meet families and patients, it just inspired me to work that much harder," he said.

The research led by UW Medicine demonstrates the potential of using multiple AAV vectors to deliver the large DMD gene, with human trials anticipated in two years. This innovative approach could significantly improve the quality of life for those affected by this devastating disease.



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