转导(生物物理学)
衣壳
遗传增强
背景(考古学)
足细胞
腺相关病毒
基因传递
肾
生物
病毒学
医学
细胞生物学
病毒
基因
载体(分子生物学)
内分泌学
蛋白尿
遗传学
生物物理学
古生物学
重组DNA
作者
Taisuke Furusho,Kei Adachi,Mia S. Galbraith-Liss,Anusha Sairavi,Ranjan Das,Hiroyuki Nakai
标识
DOI:10.1101/2023.07.28.548760
摘要
Abstract Despite recent remarkable advancements in adeno-associated virus (AAV) vector technologies, effective gene delivery to the kidney remains a significant challenge. Here we show that AAV vector transduction in proximal tubules and podocytes, the crucial targets for renal gene therapy, can be enhanced remarkably through a meticulous selection of both AAV capsids and route of administration, tailored to the condition of the kidney. In this study, we performed a side-by-side comparison of 47 AAV capsids using AAV Barcode-Seq and identified six AAV capsids, including AAV-KP1, that exhibit remarkable enhancement of renal transduction in mice when delivered locally via the renal vein or the renal pelvis. Individual capsid validation analyses revealed that local delivery of AAV-KP1, but not AAV9, enables remarkably enhanced proximal tubule transduction while minimizing off-target liver transduction. In a mouse model of chronic kidney disease, intravenous administration of AAV9, not AAV-KP1, showed efficient renal tubule and podocyte transduction, which was not observed in the control wild-type mice. We also provide evidence that these contrasting observations between AAV-KP1 and AAV9 are attributed to their distinct pharmacokinetic profiles. Thus, this study highlights the importance of context-dependent capsid selection and engineering for successful renal gene therapy.
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