Restoring vision in mice with retinal degeneration using multicharacteristic opsin

Abstract

Retinal degenerative diseases, such as retinitis pigmentosa (RP) and dry age-related macular degeneration, have led to loss of vision in millions of individuals. Currently, no surgical or medical treatment is available, although optogenetic therapies are in clinical development. We demonstrate vision restoration using multicharacteristics opsin (MCO1) in animal models with degenerated retina. MCO1 is reliably delivered to specific retinal cells via intravitreal injection of adeno-associated virus (vMCO1), leading to significant improvement in visually guided behavior conducted using a radial arm water maze. The time to reach the platform and the number of error arms decreased significantly after delivery of MCO1. Notably, the improvement in visually guided behavior was observed even at light intensity levels orders of magnitude lower than that required for channelrhodopsin-2 opsin. Viability of vMCO1-treated retina is not compromised by chronic light exposure. Safe virus-mediated MCO1 delivery has potential for effective gene therapy of diverse retinal degenerations in patients.

Laser‐assisted targeted gene delivery to degenerated retina improves retinal function

“…In order to evaluate the functional characteristics of the laser‐transfected retinal cells, a whole‐cell patch‐clamp experiment was carried out (Figure 2E). Since MCO is an ambient‐light activatable broadband opsin, [ 40 ] white light (0.015 mW/mm 2 ) was used to stimulate the MCO‐transfected retinal cells. The representative inward photocurrent profiles upon white light stimulation of the laser‐transfected cells are shown in Figure 2F for three different cells in retina explant.…”

Nano-enhanced optical gene delivery to retinal degenerated mice

“…Recently, optogenetic therapies have been evaluated for vision restoration in mice models of retinal degeneration either by non-specific stimulation of retina 26 or in a cell-specific manner for retinal ganglion cells [27][28][29][30][31] and ON bipolar cells [32][33]34 . Further, use of chloride-channel opsin (NpHR) expressing in longerpersisting cone photoreceptor protein has shown promise for restoration of vision 35 .…”

“…Herein, we introduce use of nano-enhancement of near-infrared optical field of continuous wave (CW) near-infrared (NIR) laser beam by surface plasmon resonance (SPR) near targeted retinal cells for gene delivery. To allow ambient-light based activation 34 , we utilized multi-characteristic-opsin (MCO) encoding plasmids to sensitize retinal cells in degenerated retina. It would be highly desirable to reinduce transgene expression by reinjection, and NOD provides this opportunity.…”

Bioluminescent Multi-Characteristic Opsin for monitoring visual cortical activity upon optical stimulation

“…Dysfunction of the retina, due to photoreceptor degeneration (as in Age-related macular degeneration[1-3] or Retinitis Pigmentosa[4,5]), optic nerve damage (due to Glaucoma or diabetic retinopathy), or enucleation of the eye (by combat ocular trauma[6] or traumatic optic neu-ropathy[7,8]), leads to a loss of signal transduction and/or transmission to the visual cortex. The electrical and optical stimulation methods employed in clinical trials of vision augmentation in blind patients with degenerated retinas [with intact optic nerves), involve retinal implants or external optical stimulation[9]. Recent optogenetic studies in retinal degenerated mouse models suggest that the photoreceptor-degenerated retina can be re-photosensitized, resulting in vision enhancement at ambient light levels without requiring an external stimulation source[9].…”

“…The electrical and optical stimulation methods employed in clinical trials of vision augmentation in blind patients with degenerated retinas [with intact optic nerves), involve retinal implants or external optical stimulation[9]. Recent optogenetic studies in retinal degenerated mouse models suggest that the photoreceptor-degenerated retina can be re-photosensitized, resulting in vision enhancement at ambient light levels without requiring an external stimulation source[9]. Further, in the case of severely damaged eyes or injured optic nerves, significant attempts have been made to electricalyl stimulate the primary visual cortex[10,11].…”