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Michael Berry, Amy Holt, Joshua Levitz, Autoosa Salari, John Gerard Flannery, Ehud Isacoff; Restoration of high-sensitivity and adapting vision with a cone opsin. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5198.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited and age-related retinal degenerative diseases cause progressive loss of rod and cone photoreceptors, leading to blindness, but spare downstream retinal neurons, which can be targeted for optogenetic therapy. However, optogenetic approaches have been limited either by low light sensitivity (microbial opsins and engineered receptors) or slow kinetics (ectopic retinal opsins), lack adaptation to change in ambient light, and have not been shown to restore object vision. We find that ectopic viral mediated expression of vertebrate medium wavelength cone opsin (MW-opsin) in the Retinal Ganglion cells of blind rd1 mice overcomes these limitations and supports vision in dim light.
Through AAV mediated viral expression MW-opsin is localized to the RGCs of blind rd1 mice. Retina were excised and mounded on a multielectrode array where various illumination protocols were presented. Light induced spiking responses were recorded and characterized using spike sorting software. Behavioral performance was determined using a variety of established learning and avoidance paradigms including forced two choice, stimulus paired freezing, and open field novel object exploration.
We find that, when virally delivered to retinal ganglion cells (RGCs), medium wavelength cone opsin (MW-opsin) is as sensitive enough to respond to indoor light levels but displays fast activation and decay kinetics (~300ms). MW-opsin restores light avoidance but more importantly restores discrimination between flashing and constant light and between line patterns of different orientation, in both static and moving displays on a standard LCD computer screen. We find that the light response of MW-opsin in RGCs itself also adapts to ambient light, and does so over a considerable range of ~1,000-fold, normalizing to background luminance. This “built-in” adaptation expands visual function across naturally encountered variations in lighting, from indoor to outdoor light. Finally, we find that novel object exploration in an open field environment, under conditions that depend on vision, is restored by MW-opsin, indicating that restoration of object vision under natural light.
MW-opsin provides a unique combination of speed, sensitivity, and luminance adaptation and restores key aspects of natural vision. MW-opsin therefore represents a promising new biological prosthetic for patients suffering from degenerative retinal disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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