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Journal article
A single phosphorous stereogenic center matters: Developing stereodefined PMO-gapmer antisense oligonucleotides for the treatment of tauopathies
Molecular therapy. Nucleic acids, Vol.36(2), 102519
2025
Abstract
Antisense oligonucleotides (ASOs) have been utilized for developing RNA-targeting agents that act as an inhibitor of microtubule-associated protein tau (MAPT) for the treatment of tauopathies. Although several anti-tau ASO candidates have been reported that could reduce MAPT expression either through RNase H-mediated mRNA degradation or splice switching, novel designs of chemically modified ASOs are still needed to improve their activity and safety profile. Moreover, the development of a stereodefined anti-tau ASO is highly desirable due to differences in efficacy and toxicity between diastereomers. Kunihiko Kanatsu et al.1 identified two best-performing fully stereocontrolled phosphorodiamidate morpholino oligomer (PMO) gapmers (ASO-486-R5-S and ASO-486-R5-R) targeting MAPT mRNA after performing a screening of optimal ASO sequence and subsequent screening of optimal phosphorous stereochemistry (Figure 1). Surprisingly, a dramatic difference in safety profiles between stereoisomers (ASO-409-R3-S versus ASO-409-R3-R, and ASO-409-SSR2-S versus ASO-409-SSR2-R), which only differ in one single phosphorous stereochemistry, was also observed (Figure 1). Fundamentally, this work not only revolutionizes ASO design by adopting PMO as the chemistry of wing regions in a gapmer but also highlights the importance of stereopattern screening in identifying ASO leads since as few as one phosphorous stereogenic center (generating two possible stereoisomers) matters in determining in vivo toxicity.
Details
- Title
- A single phosphorous stereogenic center matters: Developing stereodefined PMO-gapmer antisense oligonucleotides for the treatment of tauopathies
- Authors/Creators
- Suxiang Chen - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsBal Hari Poudel - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsRakesh Naduvile Veedu - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
- Publication Details
- Molecular therapy. Nucleic acids, Vol.36(2), 102519
- Publisher
- Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy.
- Number of pages
- 3
- Identifiers
- 991005774732907891
- Copyright
- © 2025 The Author(s).
- Murdoch Affiliation
- Personalised Medicine Centre
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- Citation topics
- 2 Chemistry
- 2.170 Nucleic Acids Chemistry
- 2.170.988 Oligonucleotide Modifications
- Web Of Science research areas
- Medicine, Research & Experimental
- ESI research areas
- Biology & Biochemistry