Restoring Dystrophin Protein Production in DMD With Exon Skipping AOC Therapy: Steve Hughes, MD

WATCH TIME: 4 minutes

"In the absence of functional dystrophin, muscles in patients with DMD undergo continuous damage, creating a cycle of inflammation and degeneration. Exon skipping therapy holds the potential to rescue the reading frame of dystrophin, thereby halting the muscle damage progression in certain types of DMD."

Exon skipping shows promise for treating Duchenne muscular dystrophy (DMD) as it uses antisense oligonucleotides to remove specific exons from the pre-mRNA near the mutation site, generating a usable transcript from the mutated dystrophin gene. Recent advances in RNA research and development, including utilizing antibody oligonucleotide conjugates, have enabled widespread restoration of dystrophin expression in animal models of DMD, which were achieved through single exon skipping and did not show any significant adverse effects.¹

The FDA recently granted orphan drug designation to Avidity Biosciences’ AOC 1044, an investigational treatment for DMD in patients with mutations amenable to exon 44 skipping (DMD44).¹ The therapy is being assessed in the phase 1/2 EXPLORE44 trial (NCT05670730), which plans to assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of AOC 1044 in healthy volunteers and patients with DMD44.

Recently, Steve Hughes, MD, chief medical officer at Avidity, sat down in an interview with NeurologyLive® to discuss how the absence of functional dystrophin protein can lead to progressive muscle damage seen in patients with DMD. He talked about what exon skipping therapies are and how they can address the issue of reading frame restoration in patients with the disease. In addition, Hughes spoke about the utilization of transferrin receptor-mediated delivery of oligonucleotides to improve the effectiveness of exon skipping therapy for DMD.

REFERENCES
1. Yokota T, Duddy W, Partridge T. Optimizing exon skipping therapies for DMD. Acta Myol. 2007;26(3):179-184.
2. Avidity Biosciences Receives FDA Orphan Drug Designation for AOC 1044 for Treatment of Duchenne Muscular Dystrophy in People with Mutations Amenable to Exon 44 Skipping. News Release. Avidity Biosciences. Published August 15, 2023. Accessed August 15, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-receives-fda-orphan-drug-designation-for-aoc-1044-for-treatment-of-duchenne-muscular-dystrophy-in-people-with-mutations-amenable-to-exon-44-skipping