Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing

Giulia Maule, Antonio Casini, Claudia Montagna, Anabela S. Ramalho, Kris Boeck, Zeger Debyser, Marianne S. Carlon (), Gianluca Petris () and Anna Cereseto ()
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Giulia Maule: University of Trento
Antonio Casini: University of Trento
Claudia Montagna: University of Trento
Anabela S. Ramalho: KU Leuven
Kris Boeck: KU Leuven
Zeger Debyser: KU Leuven
Marianne S. Carlon: KU Leuven
Gianluca Petris: University of Trento
Anna Cereseto: University of Trento

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11454-9

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