Delpacibart etedesiran improves the molecular pathology of myotonic dystrophy type 1 in the phase 1/2 MARINA study.

Myotonic dystrophy type 1 (DM1) is a rare, autosomal dominant, progressive neuromuscular disease caused by the expansion of CTG repeats in the DM1 protein kinase (DMPK) gene. Expanded CUG repeats in the mutant DMPK transcript bind and sequester splicing factors, especially in the muscleblind-like (MBNL) family, leading to misregulated alternative splicing of mRNA, which is the main driver of DM1 pathology. We designed an antibody-oligonucleotide conjugate (AOC), delpacibart etedesiran (del-desiran), to deliver a DMPK-targeting small interfering RNA to muscle via transferrin receptor 1-mediated cell internalization. Del-desiran reduced mutDMPK mRNA expression, increased estimated levels of functional MBNL, and corrected disease-associated mis-splicing in a dose-dependent manner. The extent of increase in functional MBNL was associated with consistent trends toward muscle function improvement, confirming del-desiran's mechanism of action and supporting its development as a treatment for DM1. The translation of its pharmacodynamic activity from preclinical models (patient-derived myotubes and Macaca fascicularis [cynomolgus monkeys]) to patients with DM1 demonstrates del-desiran's consistency across species and reveals the potential broad utility of the AOC platform in further neuromuscular diseases.