In 2017, Duchenne muscular dystrophy drug maker Sarepta signed a deal with Duke University to research potential cures for the disease using the gene-editing system CRISPR. Now the Duke lab at the center of that research pact is reporting promising results from a trial of CRISPR in mouse models of DMD.
The team, led by Duke biomedical engineering professor Charles Gersbach, Ph.D., reported that a single treatment of CRISPR in mice corrected the disease for more than a year. During that time, the mice did exhibit immune responses to the Cas9 enzyme used for gene editing, but the effects were not toxic to the animals. The researchers published their findings in the journal Nature Medicine.
The technology that Gersbach’s team tested is aimed at a mutation in the gene that produces dystrophin, a protein that’s vital for maintaining muscles’ support structure. Dystrophin is made by 79 “exons,” which are protein-coding regions that become dysfunctional when the gene is mutated.
The researchers developed a way to use CRISPR to remove dysfunctional dystrophin exons and then use DNA repair to reassemble the remaining gene. What’s left is a version of the dystrophin gene that’s shortened but still able to produce the protein.
Because of Cas9’s known potential to cause toxic off-target effects, the team observed both newborn and adult mice who received the gene-editing therapy for a full year, measuring the number of muscle cells that were edited, as well as side effects. The treatment did produce an immune response, but that “did not prevent the therapy's ability to successfully edit the dystrophin gene and produce long-term protein expression," said lead author Christopher Nelson, Ph.D., a postdoctoral fellow in Gersbach’s lab, in a statement.
Sarepta has good reason to be exploring gene editing for treating CRISPR. Its controversial DMD drug, Exondys 51, only addresses a small segment of the DMD patient population. The company has made some progress of late with an experimental gene therapy to treat the condition, but quality issues caused the FDA to put a temporary hold on a clinical trial of the treatment last summer. Still, the company is pouring more R&D cash into gene-targeted treatments, most recently shelling out $30 million to partner with Lacerta on a gene therapy for Pompe disease and two programs in rare central nervous system conditions.
Other research groups are also working on gene editing for DMD—and reporting encouraging results in animal trials. Last August, UT Southwestern researchers published research from a CRISPR trial in which dystrophin levels were restored to 92% of normal levels in dog models of DMD. A startup based on the technology, Exonics, is working toward clinical trials of the technology.
Gersbach’s team at Duke plans to focus future research on better characterizing off-target effects of CRISPR in DMD. For the new study, they mapped all the edits that occurred in the dystrophin gene. They discovered that unintended DNA sequence changes occurred about half the time.
Even though those random gene edits didn’t impact the safety or efficacy of the treatment, Nelson said, “any unintended results could potentially take away from the efficiency of the gene editing you're trying to achieve, which supports the importance of designing ways to objectively identify and mitigate alternative edits in future studies."