Eric Olson, Ph.D., founder of Exonics Therapeutics and director of UT Southwestern's Hamon Center for Regenerative Science and Medicine, has been working for the last several years to apply CRISPR gene editing to cure Duchenne muscular dystrophy (DMD). Now he’s a step closer to reaching that goal.
Olson’s team used CRISPR in dog models of DMD, restoring levels of dystrophin—a protein key to muscle function—by as much as 92% of normal levels. They published their research in the journal Science.
DMD is a genetic disease that results from a mutation in the dystrophin gene. It affects about 1 in 5,000 boys, causing gradual muscle degeneration and early heart failure. A similar mutation in dogs follows much of that same pathology.
The most recently approved DMD treatment targeting the faulty gene, Sarepta’s Exondys 51, is for the 13% of patients whose mutations are amenable to what’s known as “exon 51 skipping,” but in trials it only restored dystrophin to about 1% of normal levels.
The UT Southwestern researchers are also targeting exon 51. They used an adeno-associated virus to deliver CRISPR to the exon, and after it was edited, dystrophin levels were restored by 92% in the heart and 58% in the diaphragm, they reported. Dystrophin restoration varied in other muscle types, from 3% in the biceps to 25% in triceps to over 50% in other muscles, according to the paper.
"Our strategy is different from other therapeutic approaches for DMD because it edits the mutation that causes the disease and restores normal expression of the repaired dystrophin," said Leonela Amoasii, Ph.D., lead author of the study and assistant instructor of molecular biology in Olson's lab, in a statement.
Although Sarepta’s 2016 approval of Exondys 51 was considered a milestone at the time, the need for a more effective gene-targeting treatment was evident. Sarepta itself has more than 20 pipeline projects aimed at finding treatments that will be more broadly applicable in DMD. And in June, its stock soared on positive data from one of those: AAVrh74.MHCK7.micro-Dystrophin, a gene therapy that’s designed to be robustly expressed in heart muscle.
Solid Bio, which is also working on a DMD gene therapy, but it’s had a rough ride. The FDA slapped two clinical holds on the company’s trials, forcing Solid to change its protocol. The FDA lifted one of the holds earlier this year and the second hold in June, permitting the company to proceed with its phase 1/2 trial.
Pfizer acquired Bamboo Therapeutics for $700 million in 2016, getting ahold of a gene therapy for DMD that recently entered clinical trials.
Meanwhile, Olson’s team is working on making CRISPR a viable approach for a broader group of DMD patients. There are an estimated 3,000 mutations involved in the disease. In January, Olson’s team described a new way to correct clusters of mutations using a process called “myoediting.”
Based on the results of the most recent dog trial, Olson hopes to be able to launch a clinical trial of CRISPR in people with DMD. Exonics is also working on therapies that target exons 44, 45 and 53, in the hopes of someday being able to treat as many as 80% of patients with the disease.