Department of Chemical Engineering, The Helen Wills Neuroscience Institute, The University of California, Berkeley, CA 94720-3190, USA.
Gene Ther. 2012 Feb;19(2):176-81. doi: 10.1038/gt.2011.163. Epub 2011 Oct 20.
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.
将治疗基因递送到视网膜的大片区域，同时尽量减少眼内手术对其造成的损伤，这是治疗视网膜变性的核心目标。最近的研究表明，将 AAV9 经系统给予新生动物，可以使其到达中枢神经系统（CNS）和视网膜，这对于某些视网膜疾病来说是一种很有前景的策略。我们研究了通过突变衣壳表面的酪氨酸是否可以提高经系统给予的 AAV9 的视网膜转导效率，之前的研究表明，这可以提高几种 AAV 载体的感染性。具体来说，我们评估了新生血管内给予含有酪氨酸至苯丙氨酸突变的 AAV9 载体后对视网膜的转导。我们的结果表明，AAV9 的一种新型双酪氨酸突变显著增强了对 CNS 和视网膜的基因传递，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光感受器细胞中。这种方法为开发视网膜基因治疗或创建神经退行性疾病的动物模型提供了一种新的方法。
