Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9
Enhanced gene delivery to the neonatal retina through systemic administration of tyrosine-mutated AAV9
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DOI：
10.1038/gt.2011.163
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发表时间：
2012-02-01
期刊：
影响因子：
5.1
通讯作者：
Flannery, J. G.
中科院分区：
文献类型：
--
作者：
Dalkara, D.;Byrne, L. C.;Flannery, J. G.
将治疗基因递送至视网膜的大面积区域，同时将眼内手术造成的损伤降至最低，是视网膜变性治疗的核心目标。最近的研究表明，当对新生儿进行全身给药时，AAV9 可以到达中枢神经系统 (CNS) 和视网膜，这对于某些视网膜疾病来说是一种有前途的策略。我们研究了是否可以通过突变衣壳表面酪氨酸来提高系统递送的 AAV9 的视网膜转导效率，此前已证明衣壳表面酪氨酸可以增加几种 AAV 载体的感染性。具体来说，我们评估了新生儿血管内施用在两个高度保守位点含有酪氨酸至苯丙氨酸突变的AAV9载体后的视网膜转导。我们的结果表明，AAV9 的新型双酪氨酸突变体显着增强了向中枢神经系统和视网膜的基因递送，并且通过掺入视紫红质启动子可以将基因表达限制在视杆感光细胞中。这种方法为视网膜基因疗法的开发或神经退行性疾病动物模型的创建提供了新的方法。基因治疗 (2012) 19, 176-181; doi:10.1038/gt.2011.163； 2011 年 10 月 20 日在线发布
Delivery of therapeutic genes to a large region of the retina with minimal damage from intraocular surgery is a central goal of treatment for retinal degenerations. Recent studies have shown that AAV9 can reach the central nervous system (CNS) and retina when administered systemically to neonates, which is a promising strategy for some retinal diseases. We investigated whether the retinal transduction efficiency of systemically delivered AAV9 could be improved by mutating capsid surface tyrosines, previously shown to increase the infectivity of several AAV vectors. Specifically, we evaluated retinal transduction following neonatal intravascular administration of AAV9 vectors containing tyrosine to phenylalanine mutations at two highly conserved sites. Our results show that a novel, double tyrosine mutant of AAV9 significantly enhanced gene delivery to the CNS and retina, and that gene expression can be restricted to rod photoreceptor cells by incorporating a rhodopsin promoter. This approach provides a new methodology for the development of retinal gene therapies or creation of animal models of neurodegenerative disease. Gene Therapy (2012) 19, 176-181; doi:10.1038/gt.2011.163; published online 20 October 2011