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In 2017, the manufacturer of drugs for Duchenne Muscular Dystrophy, Sarepta, signed an agreement with Duke University to look for potential treatments for the disease with the help of the editing system. of CRISPR genes. Now, the Duke Lab at the center of this research pact is reporting promising results from a CRISPR trial in mouse models of DMD.
The team, led by Duke biomedical engineering professor Charles Gersbach, Ph.D., reported that a single CRISPR treatment in mice had corrected the disease for more than a year. During this period, mice exhibited an immune response 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 tested by the Gersbach team aims to mutate the gene that produces dystrophin, a protein essential for maintaining the muscle support structure. Dystrophin is produced by 79 "exons", which are protein-coding regions that become dysfunctional when the gene is mutated.
Researchers have developed a way to use CRISPR to eliminate dysfunctional dystrophin exons, and then use DNA repair to replenish the remaining gene. What remains is a version of the dystrophin gene that is shortened but is still able to produce the protein.
Because of the known potential of Cas9 to induce non-target toxic effects, the team observed newborn and adult mice that received the gene modification treatment for one full year, measuring the number of modified muscle cells and their side effects. The treatment actually elicited an immune response, but that "did not prevent the therapy from altering the dystrophin gene and producing long-term protein expression," said lead author Christopher Nelson. Ph.D., postdoctoral fellow at the Gersbach Laboratory, in a report.
RELATED: CRISPR stops muscular decline in DMD model in dogs
Sarepta has good reason to explore gene editing for CRISPR. Exondys 51, its controversial DMD drug, only addresses a small segment of the DMD patient population. The company has recently made progress with experimental gene therapy to treat the disease, but quality issues have led the FDA to temporarily suspend a clinical trial of treatment last summer. Nevertheless, the company is devoting more money to research and development for gene-targeted treatments, and recently donated $ 30 million to a partnership with Lacerta on gene therapy for Pompe disease and two disease programs. rare in the central nervous system.
Other research groups are also working on gene editing for DMD and are reporting encouraging results when testing on animals. Last August, researchers at UT Southwestern published a study of a CRISPR trial in which dystrophin levels had been restored to 92% of normal levels in DMD models in dogs. A technology-based startup, Exonics, is currently working on clinical trials of the technology.
Duke's Gersbach team plans to focus future research on better characterizing the untargeted effects of CRISPR in DMD. For the new study, they mapped all the changes that occurred in the dystrophin gene. They discovered that unwanted changes in the DNA sequence occurred about half the time.
Although these random genetic modifications did not affect the safety or efficacy of the treatment, Nelson said, "any unexpected results could potentially affect the effectiveness of the genetic modification you are trying to achieve; which emphasizes the importance of designing to objectively identify and mitigate possible changes in future studies. "
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