Antisense oligonucleotide splicing modulation as a novel Cystic Fibrosis therapeutic approach for the W1282X nonsense mutation

• DOI: 10.1016/j.jcf.2021.12.012
• Publication Date: 2021-12-28T22:56:50Z
• Authors: Yifat S. Oren; Ofra Avizur-Barchad; Efrat Ozeri-Galai; Renana Elgrabli; Meital R. Schirelman; Tehilla Blinder; Chava D. Stampfer; Merav Ordan; Onofrio Laselva; Malena Cohen-Cymb...; Eitan Kerem; Christine E Bear; Batsheva Kerem
• Keywords: Ivacaftor; Nonsense mutation; Exon skipping

Antisense oligonucleotide- based drugs for splicing modulation were recently approved various genetic diseases with unmet need. Here we aimed to generate skipping over exon 23 of the CFTR transcript, eliminate W1282X nonsense mutation and avoid RNA degradation induced by mediated mRNA decay mechanism, allowing production partially active proteins lacking 23.∼80 ASOs screened in 16HBEge cells. ASO candidates showing significant assessed their allele selectivity increase protein maturation function. The effect a highly potent was further analyzed well differentiated primary human nasal epithelial cells, derived from homozygous patient.ASO screening led identification several that significantly decrease level transcripts including 23. These resulted levels mature together modulators restore channel function following free uptake into these Importantly, lead ASOs, efficiently delivered uptake, able cells homozygote patient.The efficient resulting exhibiting presence modulators, demonstrate therapeutic potential benefit CF patients carrying objective advance candidate SPL23-2 proof-of-concept clinical study.