Journal article
Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation
Journal of Cystic Fibrosis, Vol.20(5), pp.P865-P875
2021
Abstract
Background
Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849+10 kb C-to-T splicing mutation in the CFTR gene.
Methods
We have screened, in FRT cells expressing the 3849+10 kb C-to-T splicing mutation, ~30 2′-O-Methyl-modified phosphorothioate ASOs, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The effect of highly potent ASO candidates on the splicing pattern, protein maturation and CFTR function was further analyzed in well differentiated primary human nasal and bronchial epithelial cells, derived from patients carrying at least one 3849+10 kb C-to-T allele.
Results
A highly potent lead ASO, efficiently delivered by free uptake, was able to significantly increase the level of correctly spliced mRNA and completely restore the CFTR function to wild type levels in cells from a homozygote patient. This ASO led to CFTR function with an average of 43% of wild type levels in cells from various heterozygote patients. Optimized efficiency of the lead ASO was further obtained with 2′-Methoxy Ethyl modification (2′MOE).
Conclusion
The highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development.
Details
- Title
- Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation
- Authors/Creators
- Y.S. Oren (Author/Creator)M. Irony-Tur Sinai (Author/Creator)A. Golec (Author/Creator)O. Barchad-Avitzur (Author/Creator)V. Mutyam (Author/Creator)Y. Li (Author/Creator)J. Hong (Author/Creator)E. Ozeri-Galai (Author/Creator)A. Hatton (Author/Creator)C. Leibson (Author/Creator)L. Carmel (Author/Creator)J. Reiter (Author/Creator)E.J. Sorscher (Author/Creator)S.D. Wilton (Author/Creator)E. Kerem (Author/Creator)S.M. Rowe (Author/Creator)I. Sermet-Gaudelus (Author/Creator)B. Kerem (Author/Creator)
- Publication Details
- Journal of Cystic Fibrosis, Vol.20(5), pp.P865-P875
- Publisher
- Elsevier B.V. on behalf of European Cystic Fibrosis Society.
- Identifiers
- 991005545512507891
- Copyright
- © 2021 The Author(s).
- 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
- 1.285 Cystic Fibrosis
- 1.285.529 CF Pathophysiology
- Web Of Science research areas
- Respiratory System
- ESI research areas
- Clinical Medicine