Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis

Rita Mejzini; Marvin H. Caruthers; Balazs Schafer; Ondrej Kostov; Kavitha Sudheendran; Marija Ciba; Mathias Danielsen; Steve Wilton; Patrick Anthony Akkari; Loren L. Flynn

doi:10.3390/ijms25158495

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Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis

Journal article

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Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis

Rita Mejzini, Marvin H. Caruthers, Balazs Schafer, Ondrej Kostov, Kavitha Sudheendran, Marija Ciba, Mathias Danielsen, Steve Wilton, Patrick Anthony Akkari and Loren L. Flynn

International journal of molecular sciences, Vol.25(15), 8495

2024

DOI: https://doi.org/10.3390/ijms25158495

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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 University
Marvin H. Caruthers - University of Colorado Boulder
Balazs Schafer
Ondrej Kostov - University of Colorado Boulder
Kavitha Sudheendran - University of Colorado Boulder
Marija Ciba - University of Colorado Boulder
Mathias Danielsen - University of Colorado Boulder
Steve Wilton - Murdoch University
Patrick Anthony Akkari - Murdoch University
Loren 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