Sarepta Investing in CRISPR Technology to Develop DMD Drugs

James Radke

Duke University and Sarepta Therapeutics are joining forces to find a new treatment for Duchenne muscular dystrophy (DMD) that involves CRISPR/Cas9 technology.

DMD is a progressive degenerative muscle disease due to low levels of the dystrophin protein as a result of mutations along the Dystrophin gene. Dystrophin acts as a shock absorber in muscle and without that protein’s support, muscles gradually die. Symptoms typically begin to appear in patients around the age of 4 or 5 years and by their teenage years, most are non-ambulatory. Few live past their 20s.

Sarepta has, until now, mostly been focused on developing their exon-skipping therapies to ‘skip over’ any mutations that occur on the Dystrophin gene to create a working, albeit shorter, dystrophin protein. The company’s FDA-approved Exondys 51 (eteplirsen) is for DMD patients amenable to exon 51 skipping therapy and their drug in development, golodirsen, is being tested in DMD patients amenable to exon 53 skipping therapy.

While skipping over the mutated gene is an option, it is a fairly crude means to fix the mutated DNA. The end result is a Dystrophin protein that may be functional but likely not fully functional. A treatment that can more precisely cut portions of the Dystrophin gene using CRISPR/Cas9 technology would be a giant leap forward for the DMD community.

At Duke University, Charles A. Gersbach, Ph.D. associate professor in the Department of Biomedical Engineering is conducting research to restore dystrophin expression by excising exons from the Dystrophin gene. Sarepta will collaborate with Dr. Gersbach’s lab to advance the CRISPR platform and take the lead in its clinical development.

Per Sarepta: “Gene editing has the potential to revolutionize the treatment of diseases with genetic mutations. We are particularly excited about the potential it holds for DMD patients,” said Douglas Ingram, Sarepta’s president and chief executive officer. “We will work closely with Dr. Gersbach, a pioneer in applying the CRISPR technology to treat Duchenne, to advance a program that builds upon the established body of research by Dr. Gersbach and his team.”

“Although early, CRISPR technology represents hope for a large percentage of individuals with DMD. Excising certain exons has the potential to correct a majority of DMD mutations. Toward that goal, we’ve shown in mouse models that we can excise exons from the dystrophin gene, leading to restoration of a functional dystrophin protein and improvements in muscle strength,” said Dr. Gersbach.

Unlike exon skipping therapy, CRISPR/Cas9 methodology can be more precise in its manipulation of the gene. Dr. Gersbach’s lab has used CRISPR/Cas9 technology to successfully manipulate the Dystrophin gene in both cell culture studies and mouse models of DMD. In the mouse models, they observed CRISPR-mediated restoration of dystrophin, improvement in muscle biochemistry, and increased muscle force.

Details of the agreement between Duke and Sarepta have not been disclosed but the signed research collaboration agreement with Duke University grants the company an option to an exclusive license to intellectual property and technology related to CRISPR/Cas9 technology developed in the laboratory of Dr. Gersbach.

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