Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Nat Commun. 2020 Jun 30;11(1):3279. doi: 10.1038/s41467-020-17047-1.
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（rAAV）目前被认为是用于人类基因治疗的最安全、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情况。在这里，我们通过高通量、长读测序描述了一种在人类临床样本中发现的新型衣壳。该衣壳，我们命名为 AAVv66，与 AAV2 具有高度相似的序列。我们证明，与 AAV2 相比，AAVv66 表现出增强的生产产量、病毒粒子稳定性和中枢神经系统转导。通过分辨率为 2.5-Å 的 cryo-EM 可视化的 AAVv66 的独特结构特性表明，在三螺旋突起和五重轴对称界面处的关键残基可能有助于 AAVv66 的有益特征。我们的研究结果强调了 AAVv66 作为基因治疗载体的潜力。
