Abstract
Photoreceptor degeneration is one of the most prevalent causes of blindness. Despite photoreceptor loss, the inner retina and central visual pathways remain intact over an extended time period, which has led to creative optogenetic approaches to restore light sensitivity in the surviving inner retina. The major drawbacks of all optogenetic tools recently developed and tested in mouse models are their low light sensitivity and lack of physiological compatibility. Here we introduce a next-generation optogenetic tool, Opto-mGluR6, designed for retinal ON-bipolar cells, which overcomes these limitations. We show that Opto-mGluR6, a chimeric protein consisting of the intracellular domains of the ON-bipolar cell–specific metabotropic glutamate receptor mGluR6 and the light-sensing domains of melanopsin, reliably recovers vision at the retinal, cortical, and behavioral levels under moderate daylight illumination.
Highlights
About one in 300 people suffer from complete or partial blindness associated with retinal degenerative diseases such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and diabetic retinopathy
Current light-sensing proteins only respond to unnaturally high light intensities and employ foreign signaling mechanisms to activate the target retinal cells
We have engineered a cell-tailored light-sensing protein called Opto-mGluR6, which responds to daylight and activates a native signaling pathway within the target cells
Summary
About one in 300 people suffer from complete or partial blindness associated with retinal degenerative diseases such as retinitis pigmentosa (RP), age-related macular degeneration (AMD), and diabetic retinopathy. Fundamental for all of the above approaches is the finding that inner retinal cell layers remain preserved for an extended time period after photoreceptor degeneration, both in human patients and in retinitis pigmentosa mouse models (rd1) [10,11]. Out of these therapeutic approaches, optogenetic gene therapy, which selectively introduces genes encoding light-sensitive proteins into surviving retinal cells to act as “replacement light sensors,” holds considerable therapeutic potential: treatment is ambulant, long-lived, and has the theoretical potential to recover high-resolution vision across the entire visual field
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