Michael T. Migawa, Wen Shen, W. Brad Wan, Guillermo Vasquez, Michael E. Oestergaard, Audrey Low, Cheryl L. De Hoyos, Ruchi Gupta, Susan Murray, Michael Tanowitz, Melanie Bell, Joshua G. Nichols, Hans Gaus, Xue-hai Liang , Eric E. Swayze, Stanley T. Crooke and Punit P. Seth
Nucleic Acids Res (2019) 47(11): 5465–5479. doi:10.1093/nar/gkz247
This study describes a strategy to improve the therapeutic profile of antisense oligonucleotides (ASOs). ASOs are achieving clinical success, but some clinical trials continue to reveal toxicities that complicate use in patients. This paper reveals a relatively simple strategy for modifying ASOs to reduce unfavorable interactions with cellular proteins and thereby lessen the likelihood that major toxicities will be encountered in patients. By precisely tuning the chemical properties of ASOs, the authors reveal several case studies for improved activity. These results may lead to a new generation in ASOs that are similar in chemical make-up and biological activity to current ASOs but possess improved properties that will enhance their clinical value.