美国哈佛大学Pardis C. Sabeti等研究人员合作通过AAV衣壳变体家族的定向进化实现跨物种的强效肌肉定向基因传递。该研究于2021年9月9日在线发表于国际一流学术期刊《细胞》。

研究人员建立了一个体内策略，用于进化和严格选择能够有效地传递到所需组织的腺相关病毒（AAV）的衣壳变体。使用这种方法，研究人员确定了一类含有RGD模体的衣壳，在小鼠和非人类灵长类动物的静脉注射后能以卓越的效率和选择性转导肌肉。

在两种遗传性肌肉疾病的小鼠模型中，研究人员证明了这些工程载体与自然发生的AAV衣壳相比，其效力和治疗效果都有很大的提高。从这种选择方法中得到的衣壳变体在各种近交系小鼠、食蟹猴和人类原始肌管中显示出保守的传递效力，其转导依赖于靶细胞表达的整合素异聚体。

据了解，替换或编辑致病突变为治疗许多人类疾病带来了巨大希望。然而，在体内将治疗性基因修饰剂传递给特定的细胞一直是一个挑战，特别是在大型的、解剖学上广泛分布的组织，如骨骼肌。

附：英文原文

Title: Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species

Author: Mohammadsharif Tabebordbar, Kim A. Lagerborg, Alexandra Stanton, Emily M. King, Simon Ye, Liana Tellez, Allison Krunnfusz, Sahar Tavakoli, Jeffrey J. Widrick, Kathleen A. Messemer, Emily C. Troiano, Behzad Moghadaszadeh, Bryan L. Peacker, Krystynne A. Leacock, Naftali Horwitz, Alan H. Beggs, Amy J. Wagers, Pardis C. Sabeti

Issue&Volume: 2021-09-09

Abstract: Replacing or editing disease-causing mutations holds great promise for treating many human diseases. Yet, delivering therapeutic genetic modifiers to specific cells in vivo has been challenging, particularly in large, anatomically distributed tissues such as skeletal muscle. Here, we establish an in vivo strategy to evolve and stringently select capsid variants of adeno-associated viruses (AAVs) that enable potent delivery to desired tissues. Using this method, we identify a class of RGD motif-containing capsids that transduces muscle with superior efficiency and selectivity after intravenous injection in mice and non-human primates. We demonstrate substantially enhanced potency and therapeutic efficacy of these engineered vectors compared to naturally occurring AAV capsids in two mouse models of genetic muscle disease. The top capsid variants from our selection approach show conserved potency for delivery across a variety of inbred mouse strains, and in cynomolgus macaques and human primary myotubes, with transduction dependent on target cell expressed integrin heterodimers.

DOI: 10.1016/j.cell.2021.08.028

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01002-3