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

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, Gregory A. Dissen and Hiroyuki Nakai ()
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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
Hiroyuki Nakai: Oregon Health & Science University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54475-9

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