Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing
Ramalho, Anabela S.
De Boeck, Kris
Nature Publishing Group UK
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Maule, G., Casini, A., Montagna, C., Ramalho, A. S., De Boeck, K., Debyser, Z., Carlon, M. S., et al. (2019). Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing. Nature Communications, 10 (1)https://doi.org/10.1038/s41467-019-11454-9
Abstract: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. The 3272–26A>G and 3849+10kbC>T CFTR mutations alter the correct splicing of the CFTR gene, generating new acceptor and donor splice sites respectively. Here we develop a genome editing approach to permanently correct these genetic defects, using a single crRNA and the Acidaminococcus sp. BV3L6, AsCas12a. This genetic repair strategy is highly precise, showing very strong discrimination between the wild-type and mutant sequence and a complete absence of detectable off-targets. The efficacy of this gene correction strategy is verified in intestinal organoids and airway epithelial cells derived from CF patients carrying the 3272–26A>G or 3849+10kbC>T mutations, showing efficient repair and complete functional recovery of the CFTR channel. These results demonstrate that allele-specific genome editing with AsCas12a can correct aberrant CFTR splicing mutations, paving the way for a permanent splicing correction in genetic diseases.
Article, /692/699/1785/4039, /631/337/4041/3196, /14/19, /13/106, /13/109, /38/22, /38/23, /38/77, /38/88, /42/44, /13/100, article
External DOI: https://doi.org/10.1038/s41467-019-11454-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/308855