Webinar Summary

• Next-generation retinal gene therapy with AAV
• Promoter design and evaluation
• Human post-mortem retinal explant culturing
• Concept of ON-bipolar cell-targeted gene therapies
• Procedure of designing a cell-type specific promoter
• Procedure of testing promoters in post-mortem retinal explant cultures
• Importance of the use of adequate experimental models

Optogenetic gene therapy holds promise to restore high-quality vision in blind patients. 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.

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.