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Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries.

Publication ,  Journal Article
Rosales, A; Blondel, LO; Hull, J; Gao, Q; Aykun, N; Peek, JL; Vargas, A; Fergione, S; Song, M; Wilson, MH; Barbas, AS; Asokan, A
Published in: Nat Biomed Eng
February 5, 2025

The difficulty of delivering genes to the kidney has limited the translation of genetic medicines, particularly for the more than 10% of the global population with chronic kidney disease. Here we show that new variants of adeno-associated viruses (AAVs) displaying robust and widespread transduction in the kidneys of mice, pigs and non-human-primates can be obtained by evolving capsid libraries via cross-species cycling in different kidney models. Specifically, the new variants, AAV.k13 and AAV.k20, were enriched from the libraries following sequential intravenous cycling through mouse and pig kidneys, ex vivo cycling in human organoid cultures, and ex vivo machine perfusion in isolated kidneys from rhesus macaques. The two variants transduced murine kidneys following intravenous administration, with selective tropism for proximal tubules, and led to markedly higher transgene expression than parental AAV9 vectors in proximal tubule epithelial cells within human organoid cultures and in autotransplanted pig kidneys. Following ureteral delivery, AAV.k20 efficiently transduced kidneys in pigs and macaques. The AAV.k13 and AAV.k20 variants are promising vectors for therapeutic gene-transfer applications in kidney diseases and transplantation.

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Published In

Nat Biomed Eng

DOI

EISSN

2157-846X

Publication Date

February 5, 2025

Location

England

Related Subject Headings

  • 4003 Biomedical engineering
 

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Rosales, A., Blondel, L. O., Hull, J., Gao, Q., Aykun, N., Peek, J. L., … Asokan, A. (2025). Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries. Nat Biomed Eng. https://doi.org/10.1038/s41551-024-01341-0
Rosales, Alan, Leo O. Blondel, Joshua Hull, Qimeng Gao, Nihal Aykun, Jennifer L. Peek, Alejandra Vargas, et al. “Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries.Nat Biomed Eng, February 5, 2025. https://doi.org/10.1038/s41551-024-01341-0.
Rosales A, Blondel LO, Hull J, Gao Q, Aykun N, Peek JL, et al. Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries. Nat Biomed Eng. 2025 Feb 5;
Rosales, Alan, et al. “Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries.Nat Biomed Eng, Feb. 2025. Pubmed, doi:10.1038/s41551-024-01341-0.
Rosales A, Blondel LO, Hull J, Gao Q, Aykun N, Peek JL, Vargas A, Fergione S, Song M, Wilson MH, Barbas AS, Asokan A. Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries. Nat Biomed Eng. 2025 Feb 5;

Published In

Nat Biomed Eng

DOI

EISSN

2157-846X

Publication Date

February 5, 2025

Location

England

Related Subject Headings

  • 4003 Biomedical engineering