Duchenne Muscular Dystrophy (DMD) is an X-linked muscular disease caused by predominantly out-of-frame mutations in the dystrophin gene that prevent the expression of a functional dystrophin protein. Dystrophin protein expression can often be restored through oligonucleotide-mediated skipping of individual DMD exons to restore the reading frame. Indeed, multiple oligonucleotides targeting different exons have been approved for treatment of DMD patients, however efficiency is limited primarily due to poor penetration of oligonucleotides to muscle tissue. Antibody-oligonucleotide conjugates (AOCs) are a novel platform designed to selectively and efficiently delivery oligonucleotides to tissues.

We evaluated the activity of an AOC in the mdx mouse model of DMD.

AOCs produced dose-dependent increases in tissue concentrations of the PMO oligonucleotide in a broad panel of muscle tissue, including the heart, in the mdx mouse model of DMD following a single dose. Evidence of pharmacologic activity as measured by exon skipping and dystrophin restoration in muscle tissue also increased in a dose-dependent manner and was maintained for at least 4 weeks. Dystrophin protein levels in gastrocnemius and heart increased by up to 30% and 8%, respectively. Importantly, AOC treatment also improved serum biomarkers of muscle damage (CK, ALT, AST) to control levels, suggesting a meaningful improvement in muscle physiology.

Data presented herein demonstrate the potent and durable activity of the AOC platform for the treatment of Duchenne Muscular Dystrophy in an animal model of the disease and provides further support and rationale to investigate its utility for clinical application.