美国斯坦福大学医学院Jan E. Carette团队近期取得重要工作进展，他们研究通过工程化受体表达介导小鼠组织特异性AAV转导。相关研究成果2023年6月8日在线发表于《自然—方法学》杂志上。

据介绍，在特定细胞类型中表达感兴趣基因的转基因小鼠模型的开发改变了人们对基本生物学和疾病的理解。然而，生成这些模型需要耗费大量的时间和资源。

研究人员开发了一种模型系统，SELective Expression and Controlled Transduction In Vivo（SELECTIV），该系统通过将腺相关病毒（AAV）载体与多血清型AAV受体AAVR的Cre诱导型过表达偶联，实现转基因的高效和特异性表达。研究人员证明，转基因AAVR过表达大大提高了许多不同细胞类型的转导效率，包括肌肉干细胞，这些细胞通常对AAV转导不敏感。通过将Cre介导的AAVR过表达与内源性AAVR的全身敲除相结合，实现了优越的特异性，这在心脏心肌细胞、肝细胞和胆碱能神经元中得到了证实。

总之，SELECTIV增强的疗效和精细特异性在开发新小鼠模型系统中具有广泛的用途，并扩大了AAV在体内基因递送中的应用。

附：英文原文

Title: Hardwiring tissue-specific AAV transduction in mice through engineered receptor expression

Author: Zengel, James, Wang, Yu Xin, Seo, Jai Woong, Ning, Ke, Hamilton, James N., Wu, Bo, Raie, Marina, Holbrook, Colin, Su, Shiqi, Clements, Derek R., Pillay, Sirika, Puschnik, Andreas S., Winslow, Monte M., Idoyaga, Juliana, Nagamine, Claude M., Sun, Yang, Mahajan, Vinit B., Ferrara, Katherine W., Blau, Helen M., Carette, Jan E.

Issue&Volume: 2023-06-08

Abstract: The development of transgenic mouse models that express genes of interest in specific cell types has transformed our understanding of basic biology and disease. However, generating these models is time- and resource-intensive. Here we describe a model system, SELective Expression and Controlled Transduction In Vivo (SELECTIV), that enables efficient and specific expression of transgenes by coupling adeno-associated virus (AAV) vectors with Cre-inducible overexpression of the multi-serotype AAV receptor, AAVR. We demonstrate that transgenic AAVR overexpression greatly increases the efficiency of transduction of many diverse cell types, including muscle stem cells, which are normally refractory to AAV transduction. Superior specificity is achieved by combining Cre-mediated AAVR overexpression with whole-body knockout of endogenous Aavr, which is demonstrated in heart cardiomyocytes, liver hepatocytes and cholinergic neurons. The enhanced efficacy and exquisite specificity of SELECTIV has broad utility in development of new mouse model systems and expands the use of AAV for gene delivery in vivo.

DOI: 10.1038/s41592-023-01896-x

Source: https://www.nature.com/articles/s41592-023-01896-x