LAUSR

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder that affects many organs. It is caused by the expansion of a cytosine-thymine-guanine (CTG) triplet repeat in the 3' untranslated region (UTR) of the human myotonic dystrophy protein kinase (hDMPK) gene, which results in a toxic gain-of-function of mutant hDMPK RNA transcripts. Antisense oligonucleotides (ASOs) have emerged in recent years as a potential gene therapy to treat DM1. However, the clinical efficacy of the systemic administration of ASOs is limited by a combination of insufficient potency and poor tissue distribution. In the present study, we assessed the potential of a new ligand-conjugated ASO (IONIS-877864; C16-HA-ASO) to target mutant hDMPK mRNA transcripts in the DMSXL mouse model of DM1. DMSXL mice were treated subcutaneously for 9 weeks with either IONIS-877864 (12.5, or 25 mg/kg) or with IONIS-486178 (12.5 or 25 mg/kg), an unconjugated ASO with the same sequence. At 25 mg/kg, IONIS-877864 significantly enhanced ASO delivery into the striated muscles of DMSXL mice following systemic administration compared to the unconjugated control. IONIS-877864 was also more efficacious than IONIS-486178, reducing mutant hDMPK transcripts by up to 92% in the skeletal muscles and 78% in the hearts of DMSXL mice. The decrease in mutant hDMPK transcripts in the skeletal muscles caused by IONIS-877864 was associated with a significant improvement in skeletal muscle strength. IONIS-877864 was non-toxic in the DMSXL mouse model. The present study showed that the C16-HA-conjugated ASO is a powerful tool for the development of a gene therapy for DM1.