Furusho Taisuke, Das Ranjan, Hakui Hideyuki, Sairavi Anusha, Adachi Kei, Galbraith-Liss Mia S, Rajagopal Pratheppa, Horikawa Masahiro, Luo Shuhua, Li Lena, Yamada Kentaro, Andeen Nicole, Dissen Gregory A, Nakai Hiroyuki
Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, Portland, OR, USA.
Dotter Department of Interventional Radiology, Oregon Health & Science University School of Medicine, Portland, OR, USA.
Nat Commun. 2024 Dec 30;15(1):10728. doi: 10.1038/s41467-024-54475-9.
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.
腺相关病毒（AAV）载体在基因治疗方面显示出前景；然而，肾脏基因转移仍然具有挑战性。在此，我们对通过不同途径给予小鼠的47种AAV衣壳进行了基于条形码测序的比较，随后进行了个体验证。我们发现，通过肾静脉或肾盂局部递送AAV-KP1而非AAV9，能够有效地转导近端小管，且肝脏脱靶转导最小，而全身性AAV9而非AAV-KP1能增强慢性肾脏病中近端小管和足细胞的转导。我们证明，这些截然不同的观察结果部分归因于它们药代动力学的差异。重要的是，我们表明在非人类灵长类动物（NHP）中，肾盂注射克服了预先存在的免疫，导致强大且专一的近端小管转导。此外，我们强调了小鼠和NHP之间肾脏转导谱的巨大差异。因此，本研究提供了机制上的见解，并强调了根据具体情况选择AAV衣壳以克服肾脏基因递送挑战的重要性。
