TY - JOUR
T1 - Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids
AU - Furusho, Taisuke
AU - Das, Ranjan
AU - Hakui, Hideyuki
AU - Sairavi, Anusha
AU - Adachi, Kei
AU - Galbraith-Liss, Mia S.
AU - Rajagopal, Pratheppa
AU - Horikawa, Masahiro
AU - Luo, Shuhua
AU - Li, Lena
AU - Yamada, Kentaro
AU - Andeen, Nicole
AU - Dissen, Gregory
AU - Nakai, Hiroyuki
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85213806064&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85213806064&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-54475-9
DO - 10.1038/s41467-024-54475-9
M3 - Article
C2 - 39737896
AN - SCOPUS:85213806064
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 10728
ER -