Gao Guangping, Vandenberghe Luk H, Wilson James M
Division of Medical Genetics, Department of Medicine, University of Pennsylvania School of Medicine, 2000, Translational Research Laboratories, 125S, 31st Street, Philadelphia, PA 19104-3403, USA.
Curr Gene Ther. 2005 Jun;5(3):285-97. doi: 10.2174/1566523054065057.
AAV based vectors can achieve stable gene transfer with minimal vector related toxicities. AAV serotype 2 (AAV2) is the first AAV that was vectored for gene transfer applications. However, the restricted tissue tropism of AAV and its low transduction efficiency have limited its further development as vector. Recent studies using vectors derived from alternative AAV serotypes such as AAV1, 4, 5 and 6 have shown improved potency and broadened tropism of the AAV vector by packaging the same vector genome with different AAV capsids. In an attempt to search for potent AAV vectors with enhanced performance profiles, molecular techniques were employed for the detection and isolation of endogenous AAVs from a variety of human and non-human primate (NHP) tissues. A family of novel primate AAVs consisting of 110 non-redundant species of proviral sequences was discovered and turned to be prevalent in 18-19% of the tissues evaluated. Phylogenetic and functional analyses revealed that primate AAVs are segregated into clades based on phylogenetic relatedness. The members within a clade share functional and serological properties. Initial evaluation in mouse models of vectors based on these novel AAVs for tissue tropism and gene transfer potency led to the identification of some vector with improved gene transfer to different target tissues. Gene therapy treatment of several mouse and canine models with novel AAV vectors achieved long term phenotypic corrections. Vectors based on new primate AAVs could become the next generation of efficient gene transfer vehicles for various gene therapy applications.
基于腺相关病毒（AAV）的载体能够以最小的载体相关毒性实现稳定的基因转移。AAV血清型2（AAV2）是首个用于基因转移应用的AAV。然而，AAV有限的组织嗜性及其低转导效率限制了其作为载体的进一步发展。最近使用源自替代AAV血清型（如AAV1、4、5和6）的载体的研究表明，通过用不同的AAV衣壳包装相同的载体基因组，AAV载体的效力得到了提高，嗜性也得到了拓宽。为了寻找性能增强的高效AAV载体，采用分子技术从多种人类和非人类灵长类动物（NHP）组织中检测和分离内源性AAV。发现了一个由110种非冗余前病毒序列组成的新型灵长类AAV家族，并且在18%至19%的评估组织中普遍存在。系统发育和功能分析表明，灵长类AAV根据系统发育相关性被分为不同的进化枝。一个进化枝内的成员具有共同的功能和血清学特性。基于这些新型AAV的载体在小鼠模型中对组织嗜性和基因转移效力的初步评估导致鉴定出一些对不同靶组织具有改善的基因转移能力的载体。用新型AAV载体对几种小鼠和犬模型进行基因治疗实现了长期的表型纠正。基于新型灵长类AAV的载体可能成为用于各种基因治疗应用的下一代高效基因转移载体。
