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

Oligonucleotides are a promising genetic medicine for myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. However, poor muscle distribution of nucleic acid drugs after systemic administration has hindered drug development, and no curative treatment exists. Additionally, DM1 pathology requires drug localization to the nucleus, where pathogenic mutant RNA is trapped, posing challenges after endocytosis and endosomal escape. Here, we show that a locked nucleic acid oligonucleotide targeting mutant CUGexp RNA tracts, conjugated to a bottlebrush polymer, exhibited improved muscle distribution and potent correction of DM1-associated splicing at low nanomolar doses in a DM1 mouse model. Significant improvements in myotonia, body weight, and grip strength were observed. The conjugates were well tolerated after 12 weeks of weekly intravenous dosing. These results suggest that bottlebrush polymer bioconjugates may overcome key limitations of traditional antisense drugs for muscular dystrophies, with the potential as potent, durable, and cost-efficient DM1 therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/668589v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@e3961corg.highwire.dtl.DTLVardef@194225dorg.highwire.dtl.DTLVardef@5c470dorg.highwire.dtl.DTLVardef@3cc46a_HPS_FORMAT_FIGEXP M_FIG C_FIG