In Vivo-Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous

被引:511
作者
Dalkara, Deniz [1 ]
Byrne, Leah C. [1 ]
Klimczak, Ryan R. [2 ]
Visel, Meike [2 ]
Yin, Lu [3 ,4 ]
Merigan, William H. [3 ,4 ]
Flannery, John G. [1 ,2 ]
Schaffer, David V. [1 ,2 ,5 ]
机构
[1] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Dept Mol & Cellular Biol, Berkeley, CA 94720 USA
[3] Univ Rochester, Flaum Eye Inst, Rochester, NY 14642 USA
[4] Univ Rochester, Ctr Visual Sci, Rochester, NY 14642 USA
[5] Univ Calif Berkeley, Dept Chem & Biomol Engn, Berkeley, CA 94720 USA
关键词
HIGH-EFFICIENCY TRANSDUCTION; LEBERS CONGENITAL AMAUROSIS; RESTORES VISUAL RESPONSES; GREEN FLUORESCENT PROTEIN; PHOTORECEPTOR CELLS; RPE65; MUTATIONS; IMMUNE-RESPONSE; VIRAL VECTORS; BIPOLAR CELLS; MOUSE RETINA;
D O I
10.1126/scitranslmed.3005708
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Inherited retinal degenerative diseases are a clinically promising focus of adeno-associated virus (AAV)-mediated gene therapy. These diseases arise from pathogenic mutations in mRNA transcripts expressed in the eye's photoreceptor cells or retinal pigment epithelium (RPE), leading to cell death and structural deterioration. Because current gene delivery methods require an injurious subretinal injection to reach the photoreceptors or RPE and transduce just a fraction of the retina, they are suitable only for the treatment of rare degenerative diseases in which retinal structures remain intact. To address the need for broadly applicable gene delivery approaches, we implemented in vivo-directed evolution to engineer AAV variants that deliver the gene cargo to the outer retina after injection into the eye's easily accessible vitreous humor. This approach has general implications for situations in which dense tissue penetration poses a barrier for gene delivery. A resulting AAV variant mediated widespread delivery to the outer retina and rescued the disease phenotypes of X-linked retinoschisis and Leber's congenital amaurosis in corresponding mouse models. Furthermore, it enabled transduction of primate photoreceptors from the vitreous, expanding its therapeutic promise.
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页数:11
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