Files and links (1)
CC BY-NC-ND V4.0, Open Access
Journal article
Thiomorpholino oligonucleotides as a robust class of next generation platforms for alternate mRNA splicing
Proceedings of the National Academy of Sciences, Vol.119(36), e2207956119
2022
Abstract
Recent advances in drug development have seen numerous successful clinical translations using synthetic antisense oligonucleotides (ASOs). However, major obstacles, such as challenging large-scale production, toxicity, localization of oligonucleotides in specific cellular compartments or tissues, and the high cost of treatment, need to be addressed. Thiomorpholino oligonucleotides (TMOs) are a recently developed novel nucleic acid analog that may potentially address these issues. TMOs are composed of a morpholino nucleoside joined by thiophosphoramidate internucleotide linkages. Unlike phosphorodiamidate morpholino oligomers (PMOs) that are currently used in various splice-switching ASO drugs, TMOs can be synthesized using solid-phase oligonucleotide synthesis methodologies. In this study, we synthesized various TMOs and evaluated their efficacy to induce exon skipping in a Duchenne muscular dystrophy (DMD) in vitro model using H2K mdx mouse myotubes. Our experiments demonstrated that TMOs can efficiently internalize and induce excellent exon 23 skipping potency compared with a conventional PMO control and other widely used nucleotide analogs, such as 2′-O-methyl and 2′-O-methoxyethyl ASOs. Notably, TMOs performed well at low concentrations (5–20 nM). Therefore, the dosages can be minimized, which may improve the drug safety profile. Based on the present study, we propose that TMOs represent a new, promising class of nucleic acid analogs for future oligonucleotide therapeutic development.
Details
- Title
- Thiomorpholino oligonucleotides as a robust class of next generation platforms for alternate mRNA splicing
- Authors/Creators
- B.T. Le (Author/Creator) - Murdoch UniversityS. Paul (Author/Creator) - Agilent Technologies (United Kingdom)K. Jastrzebska (Author/Creator) - Centrum Badań Molekularnych i Makromolekularnych Polskiej Akademii NaukH. Langer (Author/Creator) - University of Colorado BoulderM.H. Caruthers (Author/Creator) - University of Colorado BoulderR.N. Veedu (Author/Creator) - Murdoch University
- Publication Details
- Proceedings of the National Academy of Sciences, Vol.119(36), e2207956119
- Publisher
- National Academy of Sciences
- Identifiers
- 991005542115907891
- Copyright
- © 2022 The Authors.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites
Metrics
68 File views/ downloads
69 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Citation topics
- 2 Chemistry
- 2.170 Nucleic Acids Chemistry
- 2.170.988 Oligonucleotide Modifications
- Web Of Science research areas
- Chemistry, Multidisciplinary
- ESI research areas
- Chemistry