Photoreceptors and retinal pigment epithelium (RPE) cells in the outer retina are highly vulnerable to degenerative eye disease, but recent advances in optogenetics offer the possibility of restoring vision after loss of photoreceptor function. This approach has been demonstrated already in the mouse. This project will deploy a monkey model to explore the feasibility of a retinal prosthetic that bypasses degenerated photoreceptors by using optogenetic methods to make retinal ganglion cells light-sensitive. The monkey model is needed because the monkey has a fovea and human-like visual perception. To establish a monkey model of retinal degeneration, we will use phototoxicity to selectively destroy photoreceptors in localized retinal areas following exposure to bright light. We will then attempt to restore light sensitivity by transducing ganglion cells with an intravitreal injection of a viral vector designed to express channelrhodopsin. We will evaluate both the effectiveness of the light exposure in destroying photoreceptor function and the effectiveness of the optogenetic prosthesis in restoring function with two methods. First, we will measure the light responses of ganglion cells with a genetically encoded calcium indicator, imaged in the living eye with adaptive optics. The method will allow us to track ganglion cell function repeatedly over many weeks in the same monkey. Second, we will measure the visual effectiveness of the optogenetic prosthetic with visual psychophysical tasks. If these experiments are successful, they will clarify the photosensitivity, dynamic range, and information capacity of an optogenetic prosthetic applied to the primate fovea.
Although recent research holds strong promise of developing biological therapies to treat the most common and debilitating forms of eye disease, such visual prostheses have not been examined in non-human primates. This project will use an in vivo method for retinal physiology (Functional Adaptive-optics Cellular Imaging in the Living Eye or FACILE), to study the insertion of channelrhodopsin into retinal ganglion cells in order to treat blindness. The studies will be carried out in non-human primates, which can be used to determine how channelrhodopsin can restore visual perception, especially high acuity foveal vision, which is critical to human perception.
|Kotterman, M A; Yin, L; Strazzeri, J M et al. (2015) Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates. Gene Ther 22:116-26|
|Yang, Qiang; Yin, Lu; Nozato, Koji et al. (2015) Calibration-free sinusoidal rectification and uniform retinal irradiance in scanning light ophthalmoscopy. Opt Lett 40:85-8|
|Strazzeri, Jennifer M; Hunter, Jennifer J; Masella, Benjamin D et al. (2014) Focal damage to macaque photoreceptors produces persistent visual loss. Exp Eye Res 119:88-96|
|Yin, Lu; Geng, Ying; Osakada, Fumitaka et al. (2013) Imaging light responses of retinal ganglion cells in the living mouse eye. J Neurophysiol 109:2415-21|
|Sharma, Robin; Yin, Lu; Geng, Ying et al. (2013) In vivo two-photon imaging of the mouse retina. Biomed Opt Express 4:1285-93|
|Geng, Ying; Dubra, Alfredo; Yin, Lu et al. (2012) Adaptive optics retinal imaging in the living mouse eye. Biomed Opt Express 3:715-34|