Could AOC Be the Next Alternative for Duchenne Treatment?

The focus of Duchenne muscular dystrophy (DMD) drug development is shifting toward delivery efficiency. Despite the achievements of gene therapies, safety issues have been raised in some patient groups, bringing to the forefront the question of how efficiently therapeutic agents can be delivered to muscle tissue.

According to the industry on the 5th, Sarepta Therapeutics last month released three-year follow-up clinical data in ambulatory patients for Elevidys, its DMD gene therapy. In the Elevidys-treated group, the delay in functional decline, such as time to walk 10 meters and time to rise from sitting, was prolonged by about 70%. Elevidys is currently the only DMD gene therapy approved in the United States.

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DMD is a rare muscle disease caused by mutations in the dystrophin gene, and is known to occur in approximately 1 out of every 3,500 to 5,000 boys. Because dystrophin protein is not produced normally, the muscles gradually degenerate. Current standard treatment is limited to steroid therapy to suppress inflammation and slow the rate of muscle strength decline. Treatment options that directly target the root genetic cause of the disease are limited.

Elevidys is a gene therapy that uses adeno-associated virus (AAV) as a vector to deliver a functional dystrophin gene into muscle cells. However, in 2024, a non-ambulatory patient died from acute liver failure during treatment, triggering a safety controversy. The U.S. Food and Drug Administration (FDA) subsequently restricted the indication by excluding non-ambulatory patients from the treatment population. Sarepta concluded that the death was most likely due to hepatotoxicity caused by high-dose AAV administration.

In the treatment of rare muscle diseases, delivery is one of the biggest hurdles. For AAV-based gene therapies, only a small fraction of the administered therapy reaches the muscles, making high doses unavoidable to achieve sufficient efficacy. In this process, the drug burden on the liver increases, leading to toxicity risks.

The same challenge appears in approaches other than direct gene delivery. One such approach is exon skipping using oligonucleotides. Exon skipping modulates gene expression so that specific exons are skipped during dystrophin protein production. Sarepta launched a PMO-based nucleic acid therapy, but ran into the limitation of low delivery efficiency to muscle. To enhance delivery, the company developed SRP-5051, a next-generation candidate that conjugates cell-penetrating peptides (CPPs), but it discontinued development in 2024 due to long-term safety issues such as hypomagnesemia and impaired renal function.

Against this backdrop, companies that have recently drawn attention for DMD therapies commonly put a "delivery enhancement" strategy at the forefront. They judge that the key determinant of success is not the therapeutic mechanism itself, but how efficiently the therapeutic agent can be delivered to muscle tissue.

Avidity Biosciences is developing del-zota (AOC 1044), a DMD therapy designed to skip exon 44, based on its antibody-oligonucleotide conjugate (AOC) platform, which links oligonucleotides to antibodies. The program focuses on improving drug delivery efficiency into muscle tissue compared with existing exon-skipping therapies.

Dyne Therapeutics is developing DYNE-251, a DMD therapy for patients amenable to exon 51 skipping. The drug links antibody fragments to a nucleic acid therapeutic to enhance selective delivery to muscle, with the aim of improving the low muscle-targeting rate seen with conventional PMO-based therapies. Both Avidity’s and Dyne’s DMD therapies have received Breakthrough Therapy designation from the FDA.

Similar attempts are underway in Korea as well. HLB Panagene has selected DMD as the first indication to validate the applicability of an AOC platform based on peptide nucleic acid (PNA), an artificial nucleic acid.

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