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Optogenetic Vision Restoration Using Rhodopsin for Enhanced Sensitivity
Benjamin M Gaub1, Michael H Berry2, Amy E Holt2
1Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California, USA.
Abstract:
Retinal disease is one of the most active areas of gene therapy, with clinical trials ongoing in the United States for five diseases. There are currently no treatments for patients with late-stage disease in which photoreceptors have been lost. Optogenetic gene therapies are in development, but, to date, have suffered from the low light sensitivity of microbial opsins, such as channelrhodopsin and halorhodopsin, and azobenzene-based photoswitches. Several groups have shown that photoreceptive G-protein-coupled receptors (GPCRs) can be expressed heterologously, and photoactivate endogenous Gi/o signaling. We hypothesized such a GPCR could increase sensitivity due to endogenous signal amplification. We targeted vertebrate rhodopsin to retinal ON-bipolar cells of blind rd1 mice and observed restoration of: (i) light responses in retinal explants, (ii) visually-evoked potentials in visual cortex in vivo, and (iii) two forms of visually-guided behavior: innate light avoidance and discrimination of temporal light patterns in the context of fear conditioning. Importantly, both the light responses of the retinal explants and the visually-guided behavior occurred reliably at light levels that were two to three orders of magnitude dimmer than required for channelrhodopsin. Thus, gene therapy with native light-gated GPCRs presents a novel approach to impart light sensitivity for visual restoration in a useful range of illumination.
Insights
Gene therapy using vertebrate rhodopsin restored vision in blind mice at dim light levels. This novel approach offers hope for treating advanced retinal diseases by enhancing light sensitivity.
Area of Science:
- Ophthalmology
- Neuroscience
- Genetics
Background:
- Retinal diseases lack treatments for advanced stages with photoreceptor loss.
- Current optogenetic therapies have limited light sensitivity.
- Photoreceptive G-protein-coupled receptors (GPCRs) can activate endogenous signaling pathways.
Purpose of the Study:
- To investigate the potential of using vertebrate rhodopsin gene therapy for visual restoration.
- To enhance light sensitivity in retinal cells through endogenous signal amplification.
- To assess the functional recovery of vision in a mouse model of blindness.
Main Methods:
- Targeted gene therapy delivering vertebrate rhodopsin to retinal ON-bipolar cells in rd1 mice.
- Evaluation of light responses in retinal explants.
- Measurement of visually-evoked potentials in the visual cortex.
- Assessment of visually-guided behaviors, including light avoidance and pattern discrimination.
Main Results:
- Restoration of light responses in retinal explants and visually-evoked potentials in vivo.
- Successful visually-guided behaviors observed at light levels 100-1000 times dimmer than required for channelrhodopsin.
- Demonstrated functional vision restoration using native light-gated GPCRs.
Conclusions:
- Gene therapy with native light-gated GPCRs, specifically vertebrate rhodopsin, offers a promising approach for visual restoration.
- This method significantly enhances light sensitivity, enabling vision at low light levels.
- Provides a novel therapeutic strategy for patients with late-stage retinal diseases and vision loss.
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