Designer Optogenetics to Restore Vision

Leigh Spielberg MD reports from EURETINA 2021 Virtual Congress. Optogenetics offers researchers a chance to take a designer approach to restoring vision in the blind, Professor Sonja Kleinlogel told a session of the virtual conference. “Optogenetics targets photoreceptor degenerative diseases independently of the underlying pathology. This stands in contrast to gene replacement therapy, which is mutation-specific. Optogenetics turns remaining inner retina cells into replacement photoreceptors by introducing a light-sensitive protein,” Prof Kleinlogel explained. The primary indication for optogenetic therapy is retinitis pigmentosa. The optogenetic approach will probably be applied in the future for wider indications such as geographic atrophy, she predicted. Prof Kleinlogel said optogenetic vision restoration recently reached a milestone with a publication by JA Sahel and colleagues that reported the first case of partial functional recovery in a retinitis pigmentosa patient after optogenetic therapy. Their patient—injected with a microbial optogenetic tool that mainly targeted the macular ganglion cells—regained the ability to locate and count objects while using biomimetic goggles, adjusting light intensity and wavelength. “We don’t target the ganglion cells of the retina but instead the bipolar cells. [These cells] are the first-order interneurons that receive direct input from the photoreceptors. The reason for this is we want to restore the fundamental features of inner retinal signalling,” she said. “By this diversification of retinal ganglion cell output, we can restore direction selectivity, underlying motion detection, or restore the on-off channels, which indicate light getting dimmer or brighter,” Prof Kleinlogel continued. “And we can restore some aspect of light adaptation. Also, when we consider optogenetic restoration outside the fovea, targeting the bipolar cells will restore higher special resolution than targeting the ganglion cells.” The optogenetic “toolbox” requires three elements: First, the delivery vehicle, which in this case is a synthetic adeno-associated virus. Second, the optogene, for which Prof Kleinlogel’s team used a human chimeric light-sensitive protein, Opto-mGluR6. Lastly, a synthetic short promoter that is bipolar cell-specific. “In order to activate endogenous signalling in our target cells—the bipolar cells—we replaced the intercellular domains of melanopsin with those of the bipolar-specific mGluR6 receptor,” she said. This triggers endogenous mGluR6 signalling directly by light through the melanopsin photo-switch—rather than via glutamate released by the photoreceptors since these degenerate. Opto-mGluR6 is thus a light-sensitive receptor that activates endogenous bipolar cell signalling by light, obviating the need for photoreceptors. Prof Kleinlogel said intravitreal vector injection leads to very nice panretinal expression and correct subcellular protein localisation. “We have also demonstrated that our treatment is very consistent, is independent of treatment time point, and lasts until the death of the mouse.” Experimentally, functional restoration of the optomotor reflex of a fully retinal degenerated (rd1) mouse treated with Opto- GluR6 restored visual acuities, on some occasions, as high as the visual acuity and contrast sensitivity of wild-type C57BL/6 mice, Prof Kleinlogel said. “That, of course, gives us hope for humans,” Prof Kleinlogel concluded.