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J. G. Flannery; Applying Nanomedicine to Retinal Prosthetics. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4792. doi: https://doi.org/.
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Retinal degenerations cause blindness by several mechanisms culminating in the death of photoreceptor cells. Pharmacological, gene replacement, and neuroprotective strategies attempt to postpone cell death in patients with surviving photoreceptors, however many individuals are not candidates as their photoreceptors have been lost. In many retinal degenerations, inner retinal neurons survive after photoreceptor apoptosis. One strategy for restoration of light perception is by conferring light sensitivity to inner neurons in the retina. Some vision may be restored if the remaining neurons are genetically engineered to directly respond to light and signal to visual cortex.
Light-sensitive cation channels from bacteria (Channelrhodopsins) and anion pumps (Halorhodopsins) can excite and inhibit neural activity in response to light. Mammalian ion channels have been genetically engineered to add a light responsive function, specifically, shaker K+ - (‘SPARK’) for Synthetic Photoisomerizable Azobenzene Regulated Potassium channel and a light-gated ionotropic glutamate receptor (LiGluR).In addition to expression of "photoswitches" in retinal ganglion cells, restoration of light perception will require targeting these "photoswitches’ appropriately, to create a virtual ON or OFF signaling pathway. The human retina contains 30 morphologically distinct bipolar and ganglion cell subtypes; with ON and OFF-center signal detection as the most significant division among visual features extracted by ganglion cells. Imparting light sensitivity specifically to ON or OFF-center bipolar and ganglion cells with excitatory or inhibitory photoswitches may allow light perception in the absence of rod and cone-mediated vision.
We have targeted transgene expression in ON-type retinal ganglion cells in vivo. An AAV vector with a connexin-36 promoter will drive expression of the SPARK and LiGluR ion channels specifically in ON-type retinal ganglion cells in normal rat retina and the P23H rat model of rhodopsin RP. in vivo fundus imaging and confocal microscopy demonstrated gfp expression exclusively in ON-type retinal ganglion cells. The dendrites of transduced ganglion cells stratify in sublamina B of the IPL, adjacent to the ganglion cell bodies, where they make synaptic contact with the axon terminals of ON-type bipolar cells signaling increments of light.
We conclude that specific expression of excitatory and inhibitory ‘photoswitch’ in ON-type and OFF-type retinal ganglion cells is achievable, and that firing activity of these cells can be modulated by light.
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