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Journal article
Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis
International journal of molecular sciences, Vol.25(15), 8495
2024
Abstract
Pathogenic variations in the fused in sarcoma (FUS) gene are associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS). As FUS-ALS is a dominant disease, a targeted, allele-selective approach to FUS knockdown is most suitable. Antisense oligonucleotides (AOs) are a promising therapeutic platform for treating such diseases. In this study, we have explored the potential for allele-selective knockdown of FUS. Gapmer-type AOs targeted to two common neutral polymorphisms in FUS were designed and evaluated in human fibroblasts. AOs had either methoxyethyl (MOE) or thiomorpholino (TMO) modifications. We found that the TMO modification improved allele selectivity and efficacy for the lead sequences when compared to the MOE counterparts. After TMO-modified gapmer knockdown of the target allele, up to 93% of FUS transcripts detected were from the non-target allele. Compared to MOE-modified AOs, the TMO-modified AOs also demonstrated reduced formation of structured nuclear inclusions and SFPQ aggregation that can be triggered by phosphorothioate-containing AOs. How overall length and gap length of the TMO-modified AOs affected allele selectivity, efficiency and off-target gene knockdown was also evaluated. We have shown that allele-selective knockdown of FUS may be a viable therapeutic strategy for treating FUS-ALS and demonstrated the benefits of the TMO modification for allele-selective applications.
Details
- Title
- Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis
- Authors/Creators
- Rita Mejzini - Murdoch UniversityMarvin H. Caruthers - University of Colorado BoulderBalazs SchaferOndrej Kostov - University of Colorado BoulderKavitha Sudheendran - University of Colorado BoulderMarija Ciba - University of Colorado BoulderMathias Danielsen - University of Colorado BoulderSteve Wilton - Murdoch UniversityPatrick Anthony Akkari - Murdoch UniversityLoren L. Flynn - Murdoch University
- Publication Details
- International journal of molecular sciences, Vol.25(15), 8495
- Publisher
- MDPI
- Identifiers
- 991005692325507891
- Copyright
- © 2024 by the authors.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.52 Neurodegenerative Diseases
- 1.52.765 ALS Mechanisms
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary
- ESI research areas
- Chemistry