Myotonic dystrophy type 1 (DM1) is a rare, neuromuscular disease that affects multiple organ systems, and is characterized primarily by myotonia and progressive muscle wasting and weakness. DM1 has several forms, which range in age of presentation and severity, including congenital, infantile, juvenile, and adult (classic). There are more than 100,000 patients living with DM1 across the United States, Europe and Japan. The disease is inherited in an autosomal dominant pattern and is caused by a mutation called a CTG trinucleotide repeat in the dystrophia myotonica-protein kinase (DMPK) gene. Patients with DM1 experience reduced quality of life and shortened life expectancy. There are no disease modifying therapies approved for DM1.

Audentes is evaluating vectorized RNA knockdown and vectorized exon skipping to treat DM1. Both approaches are designed to prevent the accumulation of toxic DMPK RNA in affected cells, thereby restoring normal cellular function. RNA knockdown and exon skipping have both been clinically validated in studies with antisense oligonucleotides (ASOs). Combining these approaches with AAV delivery is expected to overcome the biodistribution limitations of ASO-based therapies. Preclinical studies are underway to determine the optimal construct for AT466.