Journal article
Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Nature communications, Vol.14(1), 8051
12/05/2023
DOI: 10.1038/s41467-023-43904-w
PMCID: PMC10698009
PMID: 38052872
Abstract
Gene editing strategies for cystic fibrosis are challenged by the complex barrier properties of airway epithelia. We previously reported that the amphiphilic S10 shuttle peptide non-covalently combined with CRISPR-associated (Cas) ribonucleoprotein (RNP) enabled editing of human and mouse airway epithelial cells. Here, we derive the S315 peptide as an improvement over S10 in delivering base editor RNP. Following intratracheal aerosol delivery of Cy5-labeled peptide in rhesus macaques, we confirm delivery throughout the respiratory tract. Subsequently, we target CCR5 with co-administration of ABE8e-Cas9 RNP and S315. We achieve editing efficiencies of up-to 5.3% in rhesus airway epithelia. Moreover, we document persistence of edited epithelia for up to 12 months in mice. Finally, delivery of ABE8e-Cas9 targeting the CFTR R553X mutation restores anion channel function in cultured human airway epithelia. These results demonstrate the therapeutic potential of base editor delivery with S315 to functionally correct the CFTR R553X mutation in respiratory epithelia.Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
Details
- Title: Subtitle
- Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
- Creators
- Katarina Kulhankova - University of IowaSoumba Traore - University of IowaXue Cheng - Feldan (Canada)Hadrien Benk-Fortin - Feldan (Canada)Stéphanie Hallée - Feldan (Canada)Mario Harvey - Feldan (Canada)Joannie RobergeFrédéric Couture - Oncolytics Biotech (Canada)Sajeev Kohli - Broad InstituteThomas J Gross - University of IowaDavid K Meyerholz - University of IowaGarrett R Rettig - Integrated DNA Technologies (United States)Bernice Thommandru - Integrated DNA Technologies (United States)Gavin Kurgan - Integrated DNA Technologies (United States)Christine Wohlford-Lenane - University of IowaDennis J Hartigan-O’Connor - University of California, DavisBradley P Yates - Johns Hopkins MedicineGregory A Newby - Harvard UniversityDavid R Liu - Broad InstituteAlice F Tarantal - University of California, DavisDavid GuayPaul B McCray - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.14(1), 8051
- DOI
- 10.1038/s41467-023-43904-w
- PMID
- 38052872
- PMCID
- PMC10698009
- NLM abbreviation
- Nat Commun
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group
- Grant note
- DOI: 10.13039/100000051, name: U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute, award: U24 HG010423; DOI: 10.13039/100000050, name: U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute, award: across all consortium initiatives52. Studies were also supported by U24 HG010423, P01, P01 HL152960; name: U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
- Language
- English
- Date published
- 12/05/2023
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Internal Medicine
- Record Identifier
- 9984520559702771
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