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Functional correction of CFTR mutations in human airway epithelial cells using adenine base editors.
Krishnamurthy, Sateesh; Traore, Soumba; Cooney, Ashley L; Brommel, Christian M; Kulhankova, Katarina; Sinn, Patrick L; Newby, Gregory A; Liu, David R; McCray, Paul B.
Affiliation
  • Krishnamurthy S; Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
  • Traore S; Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
  • Cooney AL; Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
  • Brommel CM; Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
  • Kulhankova K; Molecular Medicine Graduate Program, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA.
  • Sinn PL; Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
  • Newby GA; Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
  • Liu DR; Molecular Medicine Graduate Program, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA.
  • McCray PB; Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Nucleic Acids Res ; 49(18): 10558-10572, 2021 10 11.
Article in En | MEDLINE | ID: mdl-34520545
Mutations in the CFTR gene that lead to premature stop codons or splicing defects cause cystic fibrosis (CF) and are not amenable to treatment by small-molecule modulators. Here, we investigate the use of adenine base editor (ABE) ribonucleoproteins (RNPs) that convert A•T to G•C base pairs as a therapeutic strategy for three CF-causing mutations. Using ABE RNPs, we corrected in human airway epithelial cells premature stop codon mutations (R553X and W1282X) and a splice-site mutation (3849 + 10 kb C > T). Following ABE delivery, DNA sequencing revealed correction of these pathogenic mutations at efficiencies that reached 38-82% with minimal bystander edits or indels. This range of editing was sufficient to attain functional correction of CFTR-dependent anion channel activity in primary epithelial cells from CF patients and in a CF patient-derived cell line. These results demonstrate the utility of base editor RNPs to repair CFTR mutations that are not currently treatable with approved therapeutics.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Adenine / Cystic Fibrosis Transmembrane Conductance Regulator / Respiratory Mucosa / Cystic Fibrosis / Gene Editing Limits: Humans Language: En Journal: Nucleic Acids Res Year: 2021 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Adenine / Cystic Fibrosis Transmembrane Conductance Regulator / Respiratory Mucosa / Cystic Fibrosis / Gene Editing Limits: Humans Language: En Journal: Nucleic Acids Res Year: 2021 Document type: Article Affiliation country: Country of publication: