Applying CRISPR to Duchenne, Duke researchers spotlight 1-year mouse data in Sarepta-sponsored study

Charlie Gersbach (Duke University)

As Sarepta hustles its gene therapy for Duchenne muscular dystrophy into a pivotal study, one of its academic collaborators has some longterm mouse data to report on an attempt to treat the disease through gene editing.

One year after a single dose of the CRISPR-based treatment, the adult mice in the study maintained a high level of dystrophin expression, according to researchers led by Professor Charles Gersbach at Duke University.

In the study, which was sponsored by Sarepta, the NIH and several other groups, scientists used CRISPR/Cas9 to snip out dystrophin exons around the DMD-causing genetic mutation so that the body would “stitch the remaining gene back together to create a shortened — but functional — version of the dystrophin gene.” While the injection was found to trigger an immune response and induce unintended, alternative edits on the target, they didn’t turn out to be cause for concern.

Christopher Nelson

“The good news is that even though we observed both antibody and T cell responses to Cas9, neither appeared to result in any toxicity in these mice,” said Christopher Nelson, a post-doc who led the work. “The response also did not prevent the therapy’s ability to successfully edit the dystrophin gene and produce long-term protein expression.”

Nevertheless, both Gersbach and Nelson said the immune response and alternative sequence changes remain potential challenges to be monitored and overcome.

One theory emerging from these results is that editing the genes of infants before their immune systems are fully developed can circumvent any unwanted immune response, based on the observation that mice treated when they were two days old (and lacked a fully developed immune system) didn’t seem to experience an immune response to the Cas9 protein.

Moving from animal to human studies with this futuristic tech won’t be quick. Meanwhile, Sarepta — which already markets a controversial DMD treatment — is arguably in the lead of a tight race to develop a gene therapy for the disease which works by inserting a micro-dystrophin transgene via an AAV. Pfizer also has a clinical study underway, while Solid Bio is trudging along after initial biopsies suggested a flop in an early study.

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