Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis Pigmentosa

Abstract

Retinitis pigmentosa refers to a diverse group of hereditary diseases that lead to incurable blindness, affecting two million people worldwide. As a common pathology, rod photoreceptors die early, whereas light-insensitive, morphologically altered cone photoreceptors persist longer. It is unknown if these cones are accessible for therapeutic intervention. Here, we show that expression of archaebacterial halorhodopsin in light-insensitive cones can substitute for the native phototransduction cascade and restore light sensitivity in mouse models of retinitis pigmentosa. Resensitized photoreceptors activate all retinal cone pathways, drive sophisticated retinal circuit functions (including directional selectivity), activate cortical circuits, and mediate visually guided behaviors. Using human ex vivo retinas, we show that halorhodopsin can reactivate light-insensitive human photoreceptors. Finally, we identified blind patients with persisting, light-insensitive cones for potential halorhodopsin-based therapy.

Optogenetic therapy for retinitis pigmentosa

“…Their number decreases, but about 25% of cones still exist as long as 7 months after termination of rod-cone-mediated photosensitivity. 24 There is a similar dissociation of visual function and cone death in some human patients, 24 and post-mortem examination of the retinas of RP patients has revealed at least one row of foveal cones remaining in the fovea. 53,54 Preservation of human cones has not been documented in the periphery.…”

“…Patients who are legally blind are the key target population of these therapies. Three different strategies are being investigated: (1) the implantation of differentiated or undifferentiated photoreceptors, 19 (2) electronic retinal implants, [20][21][22] and (3) the subject of this review, so-called 'optogenetic' approaches, [23][24][25] which use genetically encoded light sensors to make cells light responsive. [26][27][28] The success of cellimplantation approaches depends on the formation of functional synapses between the implanted photoreceptors and endogenous bipolar cells, and on functional retinal pigment epithelium to supply photoreceptors with 11-cis-retinal.…”

“…When NpHR was expressed in light-insensitive cones in mouse models of RP, the relevant retinal ON and OFF ganglion cells were activated; light-evoked activity was measured in the cortex and visually evoked behavior was documented. 24 Importantly the result of sophisticated retinal processing, such as directional selective ganglion cell responses, has been measured in NpHR-driven retinas. One of the vectors used in this study was able to express NpHR in cones of human retinal explants, which led to hyperpolarization of human cones upon light stimulation.…”

“…One of the vectors used in this study was able to express NpHR in cones of human retinal explants, which led to hyperpolarization of human cones upon light stimulation. 24 CHOOSING AN OPTOGENETIC STRATEGY On the basis of our present knowledge, which is the best strategy that should perhaps be pursued in clinical trials? There is no simple answer to this question and, here, we discuss the advantages and limitations of each method.…”

“…Testing many different promoters in vivo in primates is not possible. Recently an in vitro model system, a post-mortem human retina preparation in culture, has been developed 24,52 that allows the investigation of gene expression from viral vectors. Although viral access to different retinal cell types is likely be different in vitro and in vivo, transducing human retina in culture allows one to make qualitative comparisons between the efficiency and specificity among different promoters.…”