New recombinant serotypes of AAV vectors

被引:404
作者
Gao, GP
Vandenberghe, LH
Wilson, JM
机构
[1] Univ Penn, Gene Therapy Program, Translat Res Labs, Div Med Genet,Dept Med,Sch Med, Philadelphia, PA 19104 USA
[2] Katholieke Univ Leuven, Gene Therapy Program, B-3000 Louvain, Belgium
关键词
AAV serotypes; AAV clades; AAV evolution; AAV sero-epidemiology; AAV vectors; gene transfer; tissue tropism; animal models;
D O I
10.2174/1566523054065057
中图分类号
Q3 [遗传学];
学科分类号
071007 [遗传学]; 090102 [作物遗传育种];
摘要
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 proper-ties. 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.
引用
收藏
页码:285 / 297
页数:13
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