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Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids

Author

Listed:
  • Taisuke Furusho

    (Oregon Health & Science University School of Medicine)

  • Ranjan Das

    (Oregon Health & Science University School of Medicine)

  • Hideyuki Hakui

    (Oregon Health & Science University School of Medicine)

  • Anusha Sairavi

    (Oregon Health & Science University School of Medicine)

  • Kei Adachi

    (Oregon Health & Science University School of Medicine)

  • Mia S. Galbraith-Liss

    (Oregon Health & Science University School of Medicine)

  • Pratheppa Rajagopal

    (Oregon Health & Science University School of Medicine)

  • Masahiro Horikawa

    (Oregon Health & Science University School of Medicine)

  • Shuhua Luo

    (Oregon Health & Science University School of Medicine)

  • Lena Li

    (Oregon Health & Science University School of Medicine)

  • Kentaro Yamada

    (Oregon Health & Science University School of Medicine)

  • Nicole Andeen

    (Oregon Health & Science University School of Medicine)

  • Gregory A. Dissen

    (Oregon Health & Science University
    Oregon Health & Science University)

  • Hiroyuki Nakai

    (Oregon Health & Science University School of Medicine
    Oregon Health & Science University
    Oregon Health & Science University School of Medicine)

Abstract

AAV vectors show promise for gene therapy; however, kidney gene transfer remains challenging. Here we conduct a barcode-seq-based comparison of 47 AAV capsids administered through different routes in mice, followed by individual validation. We find that local delivery of AAV-KP1, but not AAV9, via the renal vein or pelvis effectively transduces proximal tubules with minimal off-target liver transduction, while systemic AAV9, but not AAV-KP1, enhances proximal tubule and podocyte transduction in chronic kidney disease. We demonstrate that these contrasting observations are partly due to differences in their pharmacokinetics. Importantly, we show that renal pelvis injection overcomes pre-existing immunity, leading to robust and exclusive proximal tubule transduction, in non-human primates (NHPs). In addition, we highlight drastic differences in renal transduction profiles between mice and NHPs. Thus, this study provides mechanistic insights and underscores importance of context-dependent selection of AAV capsids to overcome challenges in gene delivery to the kidney.

Suggested Citation

  • Taisuke Furusho & Ranjan Das & Hideyuki Hakui & Anusha Sairavi & Kei Adachi & Mia S. Galbraith-Liss & Pratheppa Rajagopal & Masahiro Horikawa & Shuhua Luo & Lena Li & Kentaro Yamada & Nicole Andeen & , 2024. "Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54475-9
    DOI: 10.1038/s41467-024-54475-9
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    References listed on IDEAS

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    1. Ling Guo & Shi Luo & Zhengwu Du & Meiling Zhou & Peiwen Li & Yao Fu & Xun Sun & Yuan Huang & Zhirong Zhang, 2017. "Targeted delivery of celastrol to mesangial cells is effective against mesangioproliferative glomerulonephritis," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
    2. Amine Meliani & Florence Boisgerault & Romain Hardet & Solenne Marmier & Fanny Collaud & Giuseppe Ronzitti & Christian Leborgne & Helena Costa Verdera & Marcelo Simon Sola & Severine Charles & Alban V, 2018. "Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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    4. Jonas Weinmann & Sabrina Weis & Josefine Sippel & Warut Tulalamba & Anca Remes & Jihad El Andari & Anne-Kathrin Herrmann & Quang H. Pham & Christopher Borowski & Susanne Hille & Tanja Schönberger & No, 2020. "Identification of a myotropic AAV by massively parallel in vivo evaluation of barcoded capsid variants," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    5. Hichem Tasfaout & Christine L. Halbert & Timothy S. McMillen & James M. Allen & Theodore R. Reyes & Galina V. Flint & Dirk Grimm & Stephen D. Hauschka & Michael Regnier & Jeffrey S. Chamberlain, 2024. "Split intein-mediated protein trans-splicing to express large dystrophins," Nature, Nature, vol. 632(8023), pages 192-200, August.
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