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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.

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