Discovery and characterization of stereodefined PMO-gapmers targeting tau

• Published in: Molecular therapy. Nucleic acids 2025-03, Vol.36 (1), p.102404, Article 102404
• Main Authors: Kanatsu, Kunihiko, Takahashi, Yoshinori, Sakaguchi, Tetsuya, Kim, Dae-Shik, Murota, Miki, Shan, Mingde, Fukami, Kazuki, Itano, Wataru, Kikuta, Kenji, Yoshimura, Hikaru, Kurokawa, Toshiki, Nagayama, Yuko, Ishikawa, Rena, Dairiki, Ryo, Zhou, Zhi, Sanders, Kristen, Stupalski, Jacob, Yasui, So, Liu, Diana, Benayoud, Farid, Fang, Hui, Jing, Enxuan, Ogo, Makoto, Fang, Francis G., Wang, John, Choi, Hyeong-wook
• Format: Article
• Language: English
• Subjects: antisense oligonucleotides; gapmer; MAPT; MT: Oligonucleotides: Therapies and Applications; Original; phosphorus stereochemistry; PMO; stereodefined PMO-gapmer; stereopure oligonucleotides; tau; tauopathy
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2024.102404

Antisense oligonucleotides (ASOs) are an important class of therapeutics to treat genetic diseases, and expansion of this modality to neurodegenerative disorders has been an active area of research. To realize chronic administration of ASO therapeutics to treat neurodegenerative diseases, new chemical modifications that improve activity and safety profiles are still needed. Furthermore, it is highly desirable to develop a single stereopure ASO with a defined activity and safety profile to avoid any efficacy and safety concerns due to the batch-to-batch variation in the composition of diastereomers. Here, a stereopure PMO-gapmer was developed as a new construct to improve safety and stability by installing charge-neutral PMOs at the wing region and by fully controlling phosphorus stereochemistries. The developed stereopure PMO-gapmer construct was applied to the discovery of ASO candidates for the reduction of microtubule-associated protein tau (MAPT, tau). Sequence screening targeting MAPT followed by screening of optimal phosphorus stereochemistry identified stereopure development candidates. While evaluating the stereopure PMO-gapmers, we observed a significant difference in safety profile among stereoisomers in which only one phosphorus stereochemistry differs. These results further highlight the benefits of developing stereopure ASOs as safe and well-characterized candidates for clinical studies. [Display omitted] Kanatsu and colleagues developed a PMO-gapmer construct and a convergent solution phase synthetic method, leading to the identification of ASO-486-R5, a stereopure PMO-gapmer targeting tau. The varied safety profiles of different antisense oligonucleotide phosphorus stereoisomers underscore the importance of phosphorus stereocontrol in developing safe and effective clinical candidates.