悉尼大学John E.J. Rasko课题组研制了腺相关病毒的替代受体。2025年7月14日出版的《细胞》杂志发表了这项成果。

该团队报道了一种不同于多血清型AAV受体（AAVR）的AAV替代受体（AAVR2，羧基肽酶D [CPD]）。AAVR2使包括AAV8在内的进化系AAVs能够转导，并确定了AAV11和AAV12的独特的不依赖于AAVR的转导途径。该研究团队通过低温电镜（cryo-EM）表征了AAV8衣壳与AAVR2之间的直接结合，并鉴定了接触残留物。研究小组观察到AAV8通过其可变区VIII直接与AAVR2的羧基肽酶样结构域1结合，并证明缺乏AAVR2结合的AAV衣壳可以通过生物工程与AAVR2结合。最后，研究团队过表达一个最小功能的AAVR2来增强AAV在体内的转导。他们的研究为AAV生物学提供了见解，并提供了临床可部署的解决方案，以减少与AAV载体相关的剂量相关毒性。

据了解，以腺相关病毒（AAV）载体为主题的系统性基因治疗已被批准用于治疗几种遗传性疾病，但与高剂量载体相关的挑战和毒性仍然存在。

附：英文原文

Title: An alternate receptor for adeno-associated viruses

Author: Bijay P. Dhungel, Hua Xu, Rajini Nagarajah, Joseph Vitale, Alex C.H. Wong, Divya Gokal, Yue Feng, Mehdi Sharifi Tabar, Cynthia Metierre, Chirag Parsania, Xiaohui Song, Guopeng Wang, Xiao-dong Su, Charles G. Bailey, John E.J. Rasko

Issue&Volume: 2025-07-14

Abstract: Systemic gene therapy using adeno-associated virus (AAV) vectors is approved for the treatment of several genetic disorders, but challenges and toxicities associated with high vector doses remain. We report an alternate receptor for AAV (AAVR2, carboxypeptidase D [CPD]), which is distinct from the multi-serotype AAV receptor (AAVR). AAVR2 enables the transduction of clade E AAVs, including AAV8, and determines an exclusive AAVR-independent transduction pathway for AAV11 and AAV12. We characterized direct binding between the AAV8 capsid and AAVR2 by cryo-electron microscopy (cryo-EM) and identified contact residues. We observed that AAV8 directly binds to the carboxypeptidase-like domain 1 of AAVR2 via its variable region VIII and demonstrated that AAV capsids that lack AAVR2 binding can be bioengineered to engage with AAVR2. Finally, we overexpressed a minimal functional AAVR2 to enhance AAV transduction in vivo. Our study provides insights into AAV biology and clinically deployable solutions to reduce dose-related toxicities associated with AAV vectors.

DOI: 10.1016/j.cell.2025.06.026

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00692-0