Adeno-associated virus (AAV)-based vectors have transformed into powerful elements of genetic medicine with proven therapeutic efficacy and a good safety profile. Over the years, efforts to transduce hematopoietic stem cells (HSCs) with AAV2 vectors have, however, been challenging. While there was evidence that AAV2 delivered vector genomes to primitive, quiescent, multipotential, self-renewing, in vivo engrafting HSCs, transgene expression was elusive. In this study, we review the evolution of AAV transduction of HSC, starting with AAV2 vectors leading to the isolation of a family of naturally occurring AAVs from human CD34⁺ HSC, the AAVHSC. The stem cell-derived AAVHSCs have turned out to have remarkable potentials for genetic therapies well beyond the hematopoietic system. AAVHSCs have tropism for a wide variety of peripheral tissues, including the liver, muscle, and the retina. They cross the blood–brain barrier and transduce cells of the central nervous system. Preclinical gene therapy studies underway using AAVHSC vectors are discussed. We review the notable ability of AAVHSCs to mediate efficient, seamless homologous recombination in the absence of exogenous nuclease activity and discuss the therapeutic implications. We also discuss early results from an AAVHSC-based clinical gene therapy trial that is underway for the treatment of phenylketonuria. Thus, the stem cell-derived AAVHSC, offer a multifaceted platform for in vivo gene therapy and genome editing for the treatment of inherited diseases.

中文翻译：

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腺相关病毒和造血干细胞：腺相关病毒造血干细胞在遗传药物中的潜力。

基于腺相关病毒 (AAV) 的载体已转变为基因医学的强大元素，具有经证实的治疗效果和良好的安全性。然而，多年来，用 AAV2 载体转导造血干细胞 (HSC) 的努力一直具有挑战性。虽然有证据表明 AAV2 将载体基因组传递给原始的、静止的、多能的、自我更新的、体内移植的 HSC，但转基因表达难以捉摸。在这项研究中，我们回顾了 AAV 转导 HSC 的演变，从 AAV2 载体开始，导致从人类 CD34 ⁺HSC，AAVHSC。事实证明，干细胞衍生的 AAVHSC 在遗传治疗方面具有显着的潜力，远远超出了造血系统。AAVHSC 对多种外周组织具有趋向性，包括肝脏、肌肉和视网膜。它们穿过血脑屏障并转导中枢神经系统的细胞。讨论了正在进行的使用 AAVHSC 载体的临床前基因治疗研究。我们回顾了 AAVHSC 在没有外源核酸酶活性的情况下介导高效、无缝同源重组的显着能力，并讨论了治疗意义。我们还讨论了正在进行的用于治疗苯丙酮尿症的基于 AAVHSC 的临床基因治疗试验的早期结果。因此，干细胞衍生的 AAVHSC 为体内实验提供了一个多方面的平台。 用于治疗遗传性疾病的基因治疗和基因组编辑。