Six biotech companies working toward a cure for Duchenne muscular dystrophy (DMD) summarized their progress during an online conference session that focused on exon skipping as a way to deliver dystrophin, the protein lacking in DMD patients.

Lianna Orlando, PhD, senior director of research at CureDuchenne, moderated the panel, which was part of the nonprofit organization’s 3-day Futures 2021 event.

Presenters included Ash Dugar, PhD, senior vice president for medical affairs at Dyne Therapeutics; Leslie Magnus, MD, vice president for medical affairs at NS Pharma; Kevin Eggan, PhD, group vice president and head of research and early development at BioMarin; Deanna Tucker, PharmD, senior medical science liaison at Sarepta Therapeutics; James McArthur, PhD, president and CEO of PepGen; and Mark Stahl, PhD, senior medical director of clinical development at Avidity Biosciences.

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Despite exon skipping’s potential to directly target dystrophin, which is the root cause of DMD, it is difficult to deliver dosing high enough to get the drug into muscle without causing a toxic reaction. In addition, cardiac as well as skeletal muscle must be targeted.

“If there’s a mutation in the DNA, it can destruct the message, or the messenger RNA [mRNA], and then the dystrophin protein doesn’t get made,” Dr. Orlando explained. “What exon-skipping drugs try to do is act as a step where the DNA gets made into the mRNA in order to avoid that mutation stopping the mRNA from being made. If the exon-skipping drug works, there’s mRNA instructions to form a dystrophin protein, and that gets restored.”

Whether individual patients can benefit from exon skipping depends on which of the 79 exons in the dystrophin gene are missing or altered.

“This is a very complicated question,” Dr. Orlando said. “To start, you need to know what your specific mutation is, because exon skipping is aimed at skipping specific components of the gene, so your mutation has to correspond to that. But generally speaking, if you have a deletion in an exon adjacent to the exon being skipped, this approach might work for you.”

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The US Food and Drug Administration (FDA) has already approved therapies that target exons 45, 51, and 53. These represent a combined 29% of all Duchenne patients. In addition, other drugs now in development target those same exons as well as exon 44. “If we’re lucky to get all those across the finish line, we’d have coverage of up to 35% of DMD cases,” she said.

Exons 8, 50, 52, and 55 also have strong potential, as well as more rare phenotypes which together comprise about 30% of the DMD patient population. This means that, at least in theory, up to 80% of DMD patients have genotypes amenable to exon skipping, though the actual number may be less.

Yet even in a best-case scenario, that still leaves 20% of patients unable to benefit from the exon-skipping approach.


Exon skipping panel. Presented at: CureDuchenne 2021 Futures National Conference: October 9, 2021; Virtual.