Repairing mutation ‘clusters’ with CRISPR could lead to broader Duchenne therapy

This image of calf muscle from a DMD patient shows the displacement of muscle cells by fat cells. UT Southwestern researchers believe CRISPR gene editing could prevent this progression of the disease in many patients. (CDC)(Image: CDC)

CRISPR gene editing is an appealing prospect for Duchenne muscular dystrophy, but how it would correct the more than 3,000 different mutations behind the disorder remains a question. Researchers from UT Southwestern may have found the key: a method that corrects groups of mutations in the dystrophin gene, which could be effective in a majority of Duchenne patients.

Previous research has shown that DMD mutations tend to cluster in “hotspots” along the dystrophin gene. To take advantage of these “hotspots,” the team, led by Eric Olson, Ph.D., a professor of stem cell research at UT Southwestern, came up with an approach, dubbed “myoediting,” that corrects clusters of mutations via exon skipping.

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The scientists created heart muscle cells from induced pluripotent stem cells taken from people with different types of DMD mutations. They then carried out “myoediting” in these cells and three-dimensional engineered heart muscle. They found that correcting the mutations in just 30% to 50% of the cells resulted in restored dystrophin expression and a corresponding improvement in the mechanical force of contraction in the engineered heart muscle.

The findings, published in Science Advances, could pave the way for a broader treatment for DMD that tackles the underlying genetic cause of the disease.

DMD is caused by a range of different mutations, including large deletions, large duplications and point mutations, or mutations that affect a very small segment in a gene sequence. While the UT Southwestern team and others have used CRISPR to fix point mutations in animal models of DMD, they note in the study that under 10% of DMD patients have this type of mutation. Targeting many mutations could result in a treatment that works for as many as 60% of DMD patients, they said.

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The FDA cleared Sarepta’s Duchenne drug, Exondys 51, in 2016, but it is only indicated for the narrow band of patients whose disease is amenable to exon 51 skipping. The biotech is now working on reaching more patients with next-gen meds. It is working on golodirsen, a drug targeting a different mutation, and it has inked a deal with Duke University for the option to license its CRISPR platform for DMD.

The startup Exonics, which was founded to advance Olson’s work, is focusing on developing treatments for as many DMD patients as possible. Specifically, the company is working on therapies that skip exons 44, 45 and 53, in addition to exon 51, which would enable the treatment of 35% of known DMD mutations, Olson said. And, based on preclinical results, he thinks this approach could treat up to 80% of patients with DMD.