Ectopic Expression of a Microbial-Type Rhodopsin Restores Visual Responses in Mice with Photoreceptor Degeneration

Abstract

The death of photoreceptor cells caused by retinal degenerative diseases often results in a complete loss of retinal responses to light. We explore the feasibility of converting inner retinal neurons to photosensitive cells as a possible strategy for imparting light sensitivity to retinas lacking rods and cones. Using delivery by an adeno-associated viral vector, here, we show that long-term expression of a microbial-type rhodopsin, channelrhodopsin-2 (ChR2), can be achieved in rodent inner retinal neurons in vivo. Furthermore, we demonstrate that expression of ChR2 in surviving inner retinal neurons of a mouse with photoreceptor degeneration can restore the ability of the retina to encode light signals and transmit the light signals to the visual cortex. Thus, expression of microbial-type channelrhodopsins, such as ChR2, in surviving inner retinal neurons is a potential strategy for the restoration of vision after rod and cone degeneration.

Optogenetic therapy for retinitis pigmentosa

“…The study demonstrated ON responses in all recorded retinal ganglion cells and visually evoke potentials in the cortex. 23 Similar treatments were shown to evoke changes in behavior in rat models of RP. 43,44 Furthermore, blind transgenic mice 45 and rats 46 have been generated that express ChR2 only in a subset of ganglion cells.…”

“…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.…”

“…56 Currently, the sensitivity of optogenetically transduced cells is poor, cells providing photoresponses at high cone ranges. [23][24][25] The number of expressed sensors can be improved, for example, by using strong promoters, high AAV titers and optimal AAV serotypes for a given cell type. We are not aware, for instance, of an AAV serotype that transduces retinal bipolar cells efficiently.…”

Leveraging Optogenetic-Based Neurovascular Circuit Characterization for Repair

“…Naturally, these characteristics have also made the retina the quintessential model for the therapeutic potential of optogenetics. Several groups have shown that, following the loss of photoreceptors, light-sensitivity can be reintroduced into remaining retinal neurons using optogenetic techniques [7,8]. A similar approach could be applied to other retinal diseases, particularly those with known cell-based dysfunctions.…”

“…Optogenetics thus allows for the noninvasive activation or inhibition of specific cells with light, a method that can be leveraged to combat a wide range of neurological conditions. Already, the potential of optogenetic techniques has been demonstrated in sciatic nerve injury [2], Parkinson's disease [3], epilepsy [4], depression [5,6], and retinal degeneration [7,8]. In this work, we describe a new method of using optogenetic techniques to study retinal circuit interactions between neurons and vascular cells, and show how this general approach can be potentially applied to treat neurological diseases.…”