Recombinant adeno-associated viruses (rAAVs) are currently considered the safest and most reliable gene delivery vehicles for human gene therapy. Three serotype capsids, AAV1, AAV2, and AAV9, have been approved for commercial use in patients, but they may not be suitable for all therapeutic contexts. Here, we describe a novel capsid identified in a human clinical sample by high-throughput, long-read sequencing. The capsid, which we have named AAVv66, shares high sequence similarity with AAV2. We demonstrate that compared to AAV2, AAVv66 exhibits enhanced production yields, virion stability, and CNS transduction. Unique structural properties of AAVv66 visualized by cryo-EM at 2.5-Å resolution, suggest that critical residues at the three-fold protrusion and at the interface of the five-fold axis of symmetry likely contribute to the beneficial characteristics of AAVv66. Our findings underscore the potential of AAVv66 as a gene therapy vector.

重组腺相关病毒（rAAVs）目前被认为是人类基因治疗中最安全，最可靠的基因传递载体。三种血清型衣壳AAV1，AAV2和AAV9已被批准用于患者的商业用途，但它们可能并不适合所有治疗环境。在这里，我们描述了通过高通量，长时间阅读测序在人类临床样品中鉴定出的新型衣壳。衣壳，我们命名为AAVv66，与AAV2具有高度的序列相似性。我们证明，与AAV2相比，AAVv66表现出更高的产量，病毒体稳定性和CNS转导。在2.5Å分辨率下通过cryo-EM观察到的AAVv66的独特结构特性，提示三重突起和五重对称轴界面处的关键残基可能有助于AAVv66的有益特性。我们的发现强调了AAVv66作为基因治疗载体的潜力。