Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter

被引：149

作者：

Cronin, Therese ^{[1
,2
]}

Vandenberghe, Luk H. ^{[1
,3
]}

Hantz, Peter ^{[2
]}

Juttner, Josephine ^{[2
]}

Reimann, Andreas ^{[2
]}

Kacso, Agota-Eniko ^{[4
]}

Huckfeldt, Rachel M. ^{[1
]}

Busskamp, Volker ^{[2
,5
]}

Kohler, Hubertus ^{[2
]}

Lagali, Pamela S. ^{[2
,6
]}

Roska, Botond ^{[2
]}

Bennett, Jean ^{[1
]}

机构：

[1] Univ Penn, Scheie Eye Inst, Ctr Adv Retinal & Ophthalm Therapeut, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA

[2] Friedrich Miescher Inst Biomed Res, Basel, Switzerland

[3] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA USA

[4] Univ Babes Bolyai, Fac Phys, R-3400 Cluj Napoca, Romania

[5] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[6] Ottawa Hosp Res Inst, Regenerat Med Program, Ottawa, ON, Canada

来源：

EMBO MOLECULAR MEDICINE | 2014年 / 6卷 / 09期

基金：

瑞士国家科学基金会;

关键词：

adeno-associated virus; capsid library; multi-electrode array; optogenetics; promoter optimization; LEBER CONGENITAL AMAUROSIS; RESTORES VISUAL RESPONSES; GENE-THERAPY; DIRECTED EVOLUTION; HEPARIN-BINDING; VECTOR; TYPE-2; ROD; IDENTIFICATION; EXPRESSION;

D O I：

10.15252/emmm.201404077

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

In this report, we describe the development of a modified adeno-associated virus (AAV) capsid and promoter for transduction of retinal ON-bipolar cells. The bipolar cells, which are post-synaptic to the photoreceptors, are important retinal targets for both basic and preclinical research. In particular, a therapeutic strategy under investigation for advanced forms of blindness involves using optogenetic molecules to render ON-bipolar cells light-sensitive. Currently, delivery of adequate levels of gene expression is a limiting step for this approach. The synthetic AAV capsid and promoter described here achieves high level of optogenetic transgene expression in ON-bipolar cells. This evokes high-frequency (similar to 100Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use.

引用

页码：1175 / 1190

页数：16

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