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

Hulliger EC, Hostettler SM, Kleinlogel S

Molecular Therapy | Methods & Clinical Development · 13 Mar 2020 · doi: 10.1016/j.omtm.2020.03.003

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The authors present a crucial missing piece on the way to healing blindness: they describe a new promoter that can efficiently drive gene expression in human ON bipolar cells. Previous promotors worked well in mouse retina, but not in human retina. The new findings can pave the way to optogenetic gene therapy in blind human patients to restore functional vision. In this paper, Hulliger et al use our OptoDrum and show functional vision restoration in the rd1 mouse, a mouse model for Retinitis pigmentosa, at normal every-day light levels.

Abstract

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.