Bottlebrush Polymer Conjugates for Enhanced Antisense Oligonucleotide Therapy in Myotonic Dystrophy Type 1

However, poor muscle distribution of nucleic acid drugs following systemic administration has hindered drug development, and no curative treatment currently exists. DM1 pathology requires drug localization to the nucleus, where pathogenic mutant RNA is sequestered, posing additional challenges after cellular internalization regarding endosomal escape and nuclear uptake.

Here, we show that a locked nucleic acid oligonucleotide targeting mutant CUG repeat RNA tracts, conjugated to a bottlebrush polymer, exhibits improved muscle distribution and potent correction of DM1-associated splicing dysregulation in a DM1 mouse model. Significant improvements in myotonia, body weight, and grip strength were observed. The conjugate was well tolerated following 12 weeks of weekly intravenous administration.