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.

中文翻译：

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用于高效，安全和多功能基因治疗应用的合成工程腺相关病毒

基因疗法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。腺伴随病毒（AAV）作为基因传递载体已引起越来越多的关注，因为AAV载体安全，有效并且能够引发相对包含的免疫应答。随着FDA最近批准了两种用于治疗罕见遗传病的AAV药物，AAV载体现已投放市场，并正在进一步探索用于其他疗法。尽管在免疫特权组织中显示出希望，但由于中和抗体（nAbs）的高流行，使用AAV进行全身递送仍然受到限制。为避免nAb介导的失活，已研究了具有修饰的蛋白衣壳，束缚在衣壳表面的材料或完全封装在第二个更大的载体中的工程AAV载体。这些工程化的AAV中的许多都增加了益处，包括避免了免疫反应，克服了基因组大小限制，靶向和刺激反应性递送，以及在一个平台上对两种或多种治疗方式进行多模式治疗。天然和工程化的AAV载体已经过测试，可以治疗多种疾病，包括脊髓性肌萎缩症，视网膜疾病，癌症和组织损伤。这篇综述将涵盖AAV本身作为有前途的基因载体的优势，工程化AAV载体，特别是合成工程化AAV载体的进展和优势，以及它们在治疗中的临床翻译现状。在一个平台上采用两种或多种治疗方式的多模式疗法。天然和工程化的AAV载体已经过测试，可以治疗多种疾病，包括脊髓性肌萎缩症，视网膜疾病，癌症和组织损伤。这篇综述将涵盖AAV本身作为有前途的基因载体的优势，工程化AAV载体，特别是合成工程化AAV载体的进展和优势，以及它们在治疗中的临床翻译现状。在一个平台上采用两种或多种治疗方式的多模式疗法。天然和工程化的AAV载体已经过测试，可以治疗多种疾病，包括脊髓性肌萎缩症，视网膜疾病，癌症和组织损伤。这篇综述将涵盖AAV本身作为有前途的基因载体的优势，工程化AAV载体，特别是合成工程化AAV载体的进展和优势，以及它们在治疗中的临床翻译现状。