Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno‐associated virus capsid and promoter
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 particu...
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          | Published in | EMBO molecular medicine Vol. 6; no. 9; pp. 1175 - 1190 | 
|---|---|
| Main Authors | , , , , , , , , , , , | 
| Format | Journal Article | 
| Language | English | 
| Published | 
        London
          Nature Publishing Group UK
    
        01.09.2014
     EMBO Press Wiley Open Access Blackwell Publishing Ltd Springer Nature  | 
| Subjects | |
| Online Access | Get full text | 
| ISSN | 1757-4676 1757-4684 1757-4684  | 
| DOI | 10.15252/emmm.201404077 | 
Cover
| Abstract | 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 (~100 Hz) spiking responses in ganglion cells of previously blind,
rd1
, mice. Our vector is a promising vehicle for further development toward potential clinical use.
Synopsis
An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON‐bipolar cells, rendering them light sensitive and restoring retinal function in blind
rd1
mice.
A synthetic AAV capsid and modified bipolar‐cell specific promoter were developed to enhance transgene expression in retinal bipolar cells.
The new virus transduced at least 59% of ON‐bipolar cells in mouse retina.
In the blind
rd1
mouse the virus was used to drive expression of optogenetic channels at levels high enough to elicit strong and robust spiking responses from the ganglion cells.
This new virus‐promoter combination is thus presented as a candidate vector for clinical intervention in advanced forms of retinal degeneration.
Graphical Abstract
An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON‐bipolar cells, rendering them light sensitive and restoring retinal function in blind
rd1
mice. | 
    
|---|---|
| AbstractList | 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 (~100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use. Abstract 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 (~100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use. 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 (∼100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use. 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 (~100 Hz) spiking responses in ganglion cells of previously blind, rd1 , mice. Our vector is a promising vehicle for further development toward potential clinical use. image An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON ‐bipolar cells, rendering them light sensitive and restoring retinal function in blind rd1 mice. A synthetic AAV capsid and modified bipolar‐cell specific promoter were developed to enhance transgene expression in retinal bipolar cells. The new virus transduced at least 59% of ON ‐bipolar cells in mouse retina. In the blind rd1 mouse the virus was used to drive expression of optogenetic channels at levels high enough to elicit strong and robust spiking responses from the ganglion cells. This new virus‐promoter combination is thus presented as a candidate vector for clinical intervention in advanced forms of retinal degeneration. 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 (~100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use.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 (~100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use. 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 (~100 Hz) spiking responses in ganglion cells of previously blind, rd1 , mice. Our vector is a promising vehicle for further development toward potential clinical use. Synopsis An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON‐bipolar cells, rendering them light sensitive and restoring retinal function in blind rd1 mice. A synthetic AAV capsid and modified bipolar‐cell specific promoter were developed to enhance transgene expression in retinal bipolar cells. The new virus transduced at least 59% of ON‐bipolar cells in mouse retina. In the blind rd1 mouse the virus was used to drive expression of optogenetic channels at levels high enough to elicit strong and robust spiking responses from the ganglion cells. This new virus‐promoter combination is thus presented as a candidate vector for clinical intervention in advanced forms of retinal degeneration. Graphical Abstract An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON‐bipolar cells, rendering them light sensitive and restoring retinal function in blind rd1 mice. 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 (~100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use. 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 (~100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use. Synopsis An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON‐bipolar cells, rendering them light sensitive and restoring retinal function in blind rd1 mice. A synthetic AAV capsid and modified bipolar‐cell specific promoter were developed to enhance transgene expression in retinal bipolar cells. The new virus transduced at least 59% of ON‐bipolar cells in mouse retina. In the blind rd1 mouse the virus was used to drive expression of optogenetic channels at levels high enough to elicit strong and robust spiking responses from the ganglion cells. This new virus‐promoter combination is thus presented as a candidate vector for clinical intervention in advanced forms of retinal degeneration. An engineered genetically modified adeno‐associated virus is shown here to efficiently and specifically drive the optogenetic molecule channelrhodopsin‐2 in ON‐bipolar cells, rendering them light sensitive and restoring retinal function in blind rd1 mice.  | 
    
| Author | Kohler, Hubertus Kacsó, Ágota–Enikő Vandenberghe, Luk H Roska, Botond Hantz, Péter Huckfeldt, Rachel M Juttner, Josephine Reimann, Andreas Bennett, Jean Lagali, Pamela S Cronin, Therese Busskamp, Volker  | 
    
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25092770$$D View this record in MEDLINE/PubMed https://inserm.hal.science/inserm-02894121$$DView record in HAL  | 
    
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| Copyright | The Authors. Published under the terms of the CC BY 4.0 license 2014 2014 The Authors. Published under the terms of the CC BY 4.0 license 2014 The Authors. Published under the terms of the CC BY 4.0 license. 2014. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Distributed under a Creative Commons Attribution 4.0 International License 2014 The Authors. Published under the terms of the CC BY 4.0 license 2014  | 
    
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| DOI | 10.15252/emmm.201404077 | 
    
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| Keywords | capsid library adeno‐associated virus promoter optimization multi‐electrode array optogenetics Neuroscience adeno-associated virus promoter optimization Subject Categories Genetics Gene Therapy & Genetic Disease multi-electrode array  | 
    
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| Snippet | 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... 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... 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... Abstract In this report, we describe the development of a modified adeno‐associated virus (AAV) capsid and promoter for transduction of retinal ON‐bipolar...  | 
    
| SourceID | doaj unpaywall pubmedcentral hal proquest pubmed crossref wiley springer  | 
    
| SourceType | Open Website Open Access Repository Aggregation Database Index Database Enrichment Source Publisher  | 
    
| StartPage | 1175 | 
    
| SubjectTerms | adeno‐associated virus Animals Binding sites Bioengineering Bipolar cells Blindness capsid library Clinical trials Dependovirus - genetics EMBO16 EMBO27 Experiments Ganglion cells Gene expression Gene therapy Genetic Vectors HEK293 Cells Heparan sulfate Humans Imaging Libraries Life Sciences Light Mice Mice, Inbred C57BL multi‐electrode array Mutagenesis Mutagenesis, Site-Directed Neurobiology Neurons and Cognition optogenetics Photoreceptors promoter optimization Promoter Regions, Genetic Research Article Retina Retinal Bipolar Cells - virology Transduction, Genetic - methods Vectors (Biology)  | 
    
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| Title | Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno‐associated virus capsid and promoter | 
    
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