Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10kb C-to-T splicing mutation

• DOI: 10.1101/2021.02.14.431123
• Publication Date: 2021-02-15T06:10:18Z
• Authors: Yifat S. Oren; Michal Irony-Tur ...; Anita Golec; Ofra Barchad-Avitzur; Venkateshwar Mutyam; Yao Li; Jeong Hong; Efrat Ozeri-Galai; Aurélie Hatton; Joel Reiter; Eric J. Sorscher; Steve D. Wilton; Eitan Kerem; Steven M. Rowe; Isabelle Sermet-G...; Batsheva Kerem
• Keywords: Ivacaftor

Abstract Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently been approved various genetic diseases with unmet need. Here we aimed to develop an ASO-based therapy Cystic Fibrosis (CF) patients carrying the 3849+10kb C-to-T mutation in CFTR gene. We have screened, FRT cells expressing this mutation, ~30 ASOs chemically modified 2′-O-Methyl on a phosphrothioate backbone, targeted prevent recognition and inclusion of cryptic exon generated due mutation. The screening identified five ASO candidates able promote correct rescue channel activity. Further analyses well differentiated primary human nasal bronchial epithelial (HNEs, HBEs), derived from at least one allele, led identification highly potent lead ASO. was efficiently delivered by free uptake into patients’ HNEs HBEs completely restored function wild type levels homozygous patient 43±8% heterozygous patients. Optimized efficiency further obtained 2’-Methoxy Ethyl chemical modification. results demonstrate therapeutic potential clinical benefit caused mutations.