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Jan 21, 2016
 |  BC Innovations  |  Targets & Mechanisms

Snipping vs. skipping for DMD

Why CRISPR might be better than exon skipping for DMD

As if to preempt the regulatory setbacks in Duchenne muscular dystrophy (DMD) that last week disappointed the field, a trio of preclinical studies emerged two weeks earlier showing that cutting out DMD mutations with gene editing might offer a viable alternative to the exon-skipping strategies that have dominated the pipeline. Now, the question is whether there's reason to believe the mouse studies will translate any better to the clinic.

The studies, published Dec. 31 in Science, provide in vivoproof of concept for the first time that CRISPR-Cas9 used postnatally can have a disease-modifying effect. Despite the hype around its therapeutic promise, the technology has so far proved itself primarily in research applications, for example, in modifying cells for in vitroscreening or creating animal models of disease.

Because CRISPR allows precise removal of segments or base pairs of DNA, it lends itself well to genetic diseases such as DMD, an X-linked genetic disorder caused by thousands of different mutations in the dystrophin gene.

The most common mutations occur in exon 51 and encode premature stop codons that halt normal transcription and result in truncated, non-functional dystrophin - a protein needed for contraction and relaxation of skeletal and cardiac muscle. The lack of dystrophin leads to a progressive decline in muscle function and premature death.

Eric Olson, professor of stem cell research and chair of research on cardiac birth defects at the University of Texas Southwestern Medical Center and principal investigator on one of the studies, told BioCentury that dystrophin needs its N- and C- terminal domains, but many of the regions in between can be cut out without compromising its function.

Whereas gene editing would cut out the relevant region of the DNA, exon skipping uses antisense oligonucleotides to mask exons containing mutations, causing them to be left out during transcription. In both cases, the result is mRNA transcripts encoding the remaining segments of the gene that produce a truncated but functional form of dystrophin.

Similar to exon skipping, small molecules that promote read-through of premature stop codons during translation also produce functional dystrophin.

Two exon-skipping compounds and one small molecule are in the regulatory stages of development in the U.S. and one has been approved in Europe, but the recent announcements reflect doubt about their efficacy.

Last Thursday, FDA issued a complete response letter to BioMarin Pharmaceutical Inc. for Kyndrisa drisapersen, an antisense oligonucleotide that skips exon 51, because "substantial evidence of effectiveness" was not met. On Friday, FDA reviewers raised questions about the efficacy of eteplirsen, a phosphorodiamidate morpholino oligomer (PMO) that skips exon 51 from Sarepta Therapeutics Inc., in briefing documents released ahead of a meeting to discuss the compound's NDA.

PTC Therapeutics Inc. has also filed an NDA for Translarna ataluren, a small molecule that promotes read-through of exon 51 mutations. The molecule is already approved in the EU for DMD.

While exon skipping and gene editing share some challenges - such as making sure the therapy reaches enough cells - Amy Wagers, principal investigator on one of the Science papers, says other problems intrinsic to exon skipping are...

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