Empowering Retinal Gene Therapy with a Specific Promoter for Human Rod and Cone ON-Bipolar Cells

Hulliger, Elmar Carlos; Hostettler, Simon Manuel; Kleinlogel, Sonja (2020). Empowering Retinal Gene Therapy with a Specific Promoter for Human Rod and Cone ON-Bipolar Cells. Molecular Therapy - Methods & Clinical Development, 17, pp. 505-519. Cell Press 10.1016/j.omtm.2020.03.003

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Optogenetic gene therapy holds promise to restore high-quality vision in blind patients and recently reached clinical trials. Although the ON-bipolar cells, the first retinal interneurons, make the most attractive targets for optogenetic vision restoration, they have remained inaccessible to human gene therapy due to the lack of a robust cell-specific promoter. We describe the design and functional evaluation of 770En_454P(hGRM6), a human GRM6 gene-derived, short promoter that drives strong and highly specific expression in both the rod- and cone-type ON-bipolar cells of the human retina. Expression also in cone-type ON-bipolar cells is of importance, since the cone-dominated macula mediates high-acuity vision and is the primary target of gene therapies. 770En_454P(hGRM6)-driven middle-wave opsin expression in ON-bipolar cells achieved lasting restoration of high visual acuity in the rd1 mouse model of late retinal degeneration. The new promoter enables precise manipulation of the inner retinal network and paves the way for clinical application of gene therapies for high-resolution optogenetic vision restoration, raising hopes of significantly improving the life quality of people suffering from blindness.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology

UniBE Contributor:

Hulliger, Elmar Carlos; Hostettler, Simon Manuel and Kleinlogel, Sonja

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2329-0501

Publisher:

Cell Press

Language:

English

Submitter:

Stefan von Känel-Zimmermann

Date Deposited:

19 May 2020 16:26

Last Modified:

21 May 2020 06:23

Publisher DOI:

10.1016/j.omtm.2020.03.003

PubMed ID:

32258214

BORIS DOI:

10.7892/boris.144033

URI:

https://boris.unibe.ch/id/eprint/144033

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