Shuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo

Katarina Kulhankova, Soumba Traore, Xue Cheng, Hadrien Benk-Fortin, Stéphanie Hallée, Mario Harvey, Joannie Roberge, Frédéric Couture, Sajeev Kohli, Thomas J. Gross, David K. Meyerholz, Garrett R. Rettig, Bernice Thommandru, Gavin Kurgan, Christine Wohlford-Lenane, Dennis J. Hartigan-O’Connor, Bradley P. Yates, Gregory A. Newby, David R. Liu, Alice F. Tarantal, David Guay and Paul B. McCray ()
Additional contact information
Katarina Kulhankova: University of Iowa
Soumba Traore: University of Iowa
Xue Cheng: Feldan Therapeutics
Hadrien Benk-Fortin: Feldan Therapeutics
Stéphanie Hallée: Feldan Therapeutics
Mario Harvey: Feldan Therapeutics
Joannie Roberge: Feldan Therapeutics
Frédéric Couture: TransBIOTech, Lévis
Sajeev Kohli: Broad Institute of MIT and Harvard
Thomas J. Gross: University of Iowa
David K. Meyerholz: University of Iowa
Garrett R. Rettig: Integrated DNA Technologies
Bernice Thommandru: Integrated DNA Technologies
Gavin Kurgan: Integrated DNA Technologies
Christine Wohlford-Lenane: University of Iowa
Dennis J. Hartigan-O’Connor: School of Medicine, UC Davis
Bradley P. Yates: Johns Hopkins University School of Medicine
Gregory A. Newby: Broad Institute of MIT and Harvard
David R. Liu: Broad Institute of MIT and Harvard
Alice F. Tarantal: California National Primate Research Center, UC Davis
David Guay: Feldan Therapeutics
Paul B. McCray: University of Iowa

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-43904-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43904-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-43904-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().