FDA Approves Gene Therapy with ISCRM Origins

FDA Approves First-Ever Gene Therapy for Duchenne Muscular Dystrophy Based in Part on Technology Developed by UW Medicine/ISCRM Researchers

Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by mutations in the gene that encodes dystrophin, an essential muscle-building, shock absorbing and signaling protein. Onset of DMD, which affects about one in 5,000 male births, occurs in early childhood and leads steadily to lost mobility and life-threatening heart and diaphragm malfunctions.  While people with DMD can live into middle-age, the best therapies only alleviate symptoms and slow progression of the disease.

Faculty headshot of Jeffrey Chamberlain, PhD
ISCRM Faculty Member Jeff Chamberlain, PhD

For the last thirty years ISCRM faculty member Jeff Chamberlain, PhD has been part of an effort to fix the underlying problems by using a harmless virus to carry a synthetic, miniaturized version of the gene to cells (dystrophin is the largest known human gene).

On June 22, 2023, the FDA approved the first-ever gene therapy for DMD – an approach to treating the disease, developed by Sarepta Therapeutics, that is based in part on technology designed by Chamberlain and his collaborators at UW Medicine. Approval for the treatment was limited to boys aged 4-5.

Dr. Chamberlain is a Professor of Neurology, Biochemistry, Medicine/Medical Genetics and the McCaw Chair in Muscular Dystrophy, a Director of the Wellstone Center (with Dr. Stephen Tapscott as co-director), and President of the American Society of Gene and Cell Therapy.  The Wellstone Center is currently funded by a five-year $7.5 million dollar award from the National Institute for Arthritis, Musculoskeletal, and Skin Diseases (NIAMS), and supports translational research into developing treatments for DMD and FSHD.

The technology behind the promising treatment is known as AAV Vector gene therapy. Preparing the treatment for use in humans has been a decades-long process. In a series of milestones, researchers at the Wellstone Center identified a method for gene delivery that reached all the muscles in the body, showed that this strategy was effective at suppressing the disease in mice, learned to compress the dystrophin gene, and devised a system to regulate the amount of protein the gene produced in cells.

Chamberlain credits fellow ISCRM faculty member Stephen Hauschka, PhD for crucial contributions to the efficacy and the safety of the DMD gene therapy. “Steve and his lab, who are world leaders in transcriptional control of muscle genes, helped ensure that the gene therapy would target muscle cells, and not the liver or other tissues, in a miniaturized gene regulatory cassette engineered to precisely deliver the micro-dystrophin.”

Beyond its connection to the Sarepta therapy, the vector technology has been licensed to the biotech company Solid Biosciences, which has entered it in human clinical trials. Genethon, Regenxbio, Pfizer, and Roche are also conducting clinical trials of gene therapies for DMD.

“I’m excited to see a therapy for DMD clear this hurdle,” says Chamberlain. “It’s really important to help these kids as soon as possible because it’s a very progressive disease. And the older they get the more muscle they lose, the more damage is done. And it becomes increasingly harder to treat the disease.”

In the meantime, while the research community and patient families await further data from ongoing trials, UW Medicine scientists like Chamberlain are continuing to pursue and test improvements to the AAV Vector gene therapy. Chamberlain says he and his collaborators are focused on more efficient delivery vehicles, better gene regulatory cassettes, and more functional versions of dystrophin.