ACS Nano. 2020 Nov 24;14(11):14262-14283. doi: 10.1021/acsnano.0c03850. Epub 2020 Oct 19.
Gene therapy directly targets mutations causing disease, allowing for a specific treatment at a molecular level. Adeno-associated virus (AAV) has been of increasing interest as a gene delivery vehicle, as AAV vectors are safe, effective, and capable of eliciting a relatively contained immune response. With the recent FDA approval of two AAV drugs for treating rare genetic diseases, AAV vectors are now on the market and are being further explored for other therapies. While showing promise in immune privileged tissue, the use of AAV for systemic delivery is still limited due to the high prevalence of neutralizing antibodies (nAbs). To avoid nAb-mediated inactivation, engineered AAV vectors with modified protein capsids, materials tethered to the capsid surface, or fully encapsulated in a second, larger carrier have been explored. Many of these engineered AAVs have added benefits, including avoided immune response, overcoming the genome size limit, targeted and stimuli-responsive delivery, and multimodal therapy of two or more therapeutic modalities in one platform. Native and engineered AAV vectors have been tested to treat a broad range of diseases, including spinal muscular atrophy, retinal diseases, cancers, and tissue damage. This review will cover the benefits of AAV as a promising gene vector by itself, the progress and advantages of engineered AAV vectors, particularly synthetically engineered ones, and the current state of their clinical translation in therapy.
基因治疗直接针对导致疾病的突变，从而可以在分子水平上进行特异性治疗。腺相关病毒（AAV）作为一种基因传递载体越来越受到关注，因为 AAV 载体安全、有效，并能够引起相对局限的免疫反应。最近 FDA 批准了两种用于治疗罕见遗传疾病的 AAV 药物，AAV 载体现已上市，并正在进一步探索用于其他疗法。虽然在免疫特权组织中显示出前景，但由于中和抗体（nAb）的高发生率，AAV 用于全身递送的应用仍然受到限制。为了避免 nAb 介导的失活，已经探索了具有修饰的蛋白衣壳、与衣壳表面连接的材料或完全封装在第二个更大载体中的工程化 AAV 载体。许多这些工程化的 AAV 具有额外的益处，包括避免免疫反应、克服基因组大小限制、靶向和刺激响应性递送，以及在一个平台上对两种或更多治疗方式进行多模态治疗。天然和工程化的 AAV 载体已被用于治疗广泛的疾病，包括脊髓性肌萎缩症、视网膜疾病、癌症和组织损伤。本综述将介绍 AAV 作为一种有前途的基因载体的自身优势、工程化 AAV 载体的进展和优势，特别是合成工程化 AAV 载体的优势，以及它们在治疗中的临床转化现状。
