Authors
Yao Li, Christopher Oetheimer, Yuyan Wang, Gyu Seong Heo, Jiaqi Wu, Rong Chang, Wei Zhang, Elle Schneider, Junjie Chen, Yang Fang, Yun Wei, Keqing Nian, Hengli Zhang, Lauren Sherman, Yongjian Liu, Ke Zhang
Published in
Nucleic acids research. Volume 54. Issue 12. Jun 22, 2026.
Abstract
Oligonucleotides are a promising class of genetic medicine for myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. 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. These findings suggest that bottlebrush polymer conjugates may overcome key limitations of conventional oligonucleotide therapeutics for neuromuscular conditions, with potential to become a potent and cost-effective DM1 therapy.
PMID:
42339623
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.
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