Novel Properties of Tyrosine-mutant AAV2 Vectors in the Mouse Retina
Novel Properties of Tyrosine-mutant AAV2 Vectors in the Mouse Retina
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DOI：
10.1038/mt.2010.234
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发表时间：
2011-02-01
影响因子：
12.4
通讯作者：
Hauswirth, William W.
中科院分区：
文献类型：
--
作者：
Petrs-Silva, Hilda;Dinculescu, Astra;Hauswirth, William W.
基于腺相关病毒血清型2（AAV 2）的载体已广泛用于许多基因递送应用，包括针对视网膜中的一种类型的Leber先天性黑蒙的几个成功的临床试验。许多研究集中在通过基因工程改造其衣壳来提高AAV2的转导效率和细胞特异性。我们先前已经表明，与其野生型对应物相比，在血清型AAV2、AAV8和AAV9中含有衣壳表面酪氨酸的单点突变的载体在视网膜中显示出显著增加的转导效率。在本研究中，我们评估了在成年小鼠视网膜下或玻璃体内递送后，在7个高度保守的表面暴露的衣壳酪氨酸残基中含有多个酪氨酸至苯丙氨酸突变的组合的AAV2载体的转导特性。多重突变的载体表现出不同的体内转导特性，其中一些具有在所有视网膜层中表达转基因的独特能力。这种新的载体可用于开发用于治疗许多遗传疾病的有价值的新治疗策略。
Vectors based on adeno-associated virus serotype 2 (AAV2) have been used extensively in many gene-delivery applications, including several successful clinical trials for one type of Leber congenital amaurosis in the retina. Many studies have focused on improving AAV2 transduction efficiency and cellular specificity by genetically engineering its capsid. We have previously shown that vectors-containing single-point mutations of capsid surface tyrosines in serotypes AAV2, AAV8, and AAV9 displayed significantly increased transduction efficiency in the retina compared with their wild-type counterparts. In the present study, we evaluated the transduction characteristics of AAV2 vectors containing combinations of multiple tyrosine to phenylalanine mutations in seven highly conserved surface-exposed capsid tyrosine residues following subretinal or intravitreal delivery in adult mice. The multiply mutated vectors exhibited different in vivo transduction properties, with some having a unique ability of transgene expression in all retinal layers. Such novel vectors may be useful in developing valuable new therapeutic strategies for the treatment of many genetic diseases.