Journal
NUCLEIC ACIDS RESEARCH
Volume 49, Issue 18, Pages 10558-10572Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab788
Keywords
-
Categories
Funding
- National Institutes of Health [P01 HL133089, UG3 HL147366, HL133089, P01 HL51670, P01 HL152960, U24 HG010423, UG3 AI150551, U01 AI142756, R35 GM118062, UG3 TR002636]
- Center for Gene Therapy of Cystic Fibrosis [P30 DK54759]
- Cystic Fibrosis Foundation [MCCRAY15XX0, SINN19XX0, COONEY18F0]
- Helen Hay Whitney postdoctoral fellowship
- HHMI.
- Roy J. Carver Charitable Trust
Ask authors/readers for more resources
The study found that using adenine base editor RNPs can successfully correct certain gene mutations causing CF, with repair efficiencies reaching 38-82%, achieving functional correction of CFTR-dependent channel activity.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available