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Antisense oligonucleotide induced exon skipping to restore the CFTR reading frame

Martinovich, K., Kicic, A., Fletcher, S., Wilton, S. and Stick, S. (2021) Antisense oligonucleotide induced exon skipping to restore the CFTR reading frame. Respirology, 26 (Supp. 2). p. 23.

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Current CFTR modulator therapies for cystic fibrosis (CF) act upon the CFTR protein to improve conformation and function. Although 90% of people with CF have a genotype that can benefit from these treatments, some of the remaining 10% have nonsense or frameshift mutations that result in premature termination of protein translation and nonsense mediated decay (NMD). These mutations result in no CFTR protein being produced, and therefore no benefit will be derived from CFTR modulating drugs. One potential complementary therapeutic strategy is antisense oligonucleotide (AO) mediated splice modulation. The AOs are synthetic RNA analogues designed to anneal to selected splice motifs within the pre-mRNA. The binding of an AO alters the recognition of the splice site or motif by the spliceosome and therefore modulates exon selection. We hypothesize that skipping of selected exons using AOs in people with CF caused by NMD-prone mutations such as p.Glu92X(exon 4), p.Tyr275X(exon 7), p.Phe861Leufsx3(exon 15) or c.2989-1G>A(exon 18) the premature termination of translation can be avoided. The protein isoform generated from the induced RNA isoform may become amenable to CFTR modulators.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: Wiley-Blackwell
Copyright: © 2021 Asian Pacific Society of Respirology.
Other Information: Oral abstract taken from TSANZSRS 2021 The Australia & New Zealand Society of Respiratory Science and The Thoracic Society of Australia and New Zealand (ANZSRS/TSANZ) Annual Scientific Meeting for Leaders in Lung Health & Respiratory Science, 1–2 May 2021
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