Gene Therapy Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7352, USA.
Mol Ther. 2012 Apr;20(4):699-708. doi: 10.1038/mt.2011.287. Epub 2012 Jan 24.
The discovery of naturally occurring adeno-associated virus (AAV) isolates in different animal species and the generation of engineered AAV strains using molecular genetics tools have yielded a versatile AAV vector toolkit. Promising results in preclinical animal models of human disease spurred the much awaited transition toward clinical application, and early successes in phase I/II clinical trials for a broad spectrum of genetic diseases have recently been reported. As the gene therapy community forges ahead with cautious optimism, both preclinical and clinical studies using first generation AAV vectors have highlighted potential challenges. These include cross-species variation in vector tissue tropism and gene transfer efficiency, pre-existing humoral immunity to AAV capsids and vector dose-dependent toxicity in patients. A battery of second generation AAV vectors, engineered through rational and combinatorial approaches to address the aforementioned concerns, are now available. This review will provide an overview of preclinical studies with the ever-expanding AAV vector portfolio in large animal models and an update on new lead AAV vector candidates poised for clinical translation.
在不同动物物种中发现天然存在的腺相关病毒（AAV）分离株，以及使用分子遗传学工具生成工程 AAV 株，为多功能 AAV 载体工具包提供了可能。在人类疾病的临床前动物模型中取得的有希望的结果促使人们急切地期待向临床应用的转变，最近报道了针对广泛遗传疾病的 I/II 期临床试验的早期成功。随着基因治疗界谨慎乐观地前进，使用第一代 AAV 载体的临床前和临床研究都突出了潜在的挑战。这些挑战包括载体组织嗜性和基因转移效率的跨物种差异、对 AAV 衣壳的预先存在的体液免疫和患者中载体剂量依赖性毒性。现在有一系列通过合理和组合方法设计的第二代 AAV 载体，旨在解决上述问题。本文将综述在大型动物模型中使用不断扩展的 AAV 载体组合进行的临床前研究，并更新即将进行临床转化的新型领先 AAV 载体候选物。
