A Gene Therapy Restores Some Degree of Vision in Mice with Retinal Degeneration

The paper I'll point out here is an excellent example of the glacial pace of many lines of research. Years can pass between studies that look very similar, and one wonders what has been taking place in between, if anything. It has been nearly ten years since I first pointed out a study demonstrating partial restoration of visual function - at least sensing of light and darkness in the visual field - in mice with retinal degeneration. A gene therapy was used to produce expression of the protein melanopsin in retinal cells where it is usually absent. This in turn allowed these cells to participate in the light-sensing activity of the retina, where usually they would not. In effect it was providing a sort of rudimentary backup to the photoreceptor cells that are lost in degenerative conditions affecting the retina.

This week, a new paper has arrived to document a recent study of melanopsin gene therapy in which the only real differences from the study conducted a decade ago are that the mice are followed for longer after the procedure, a year, a more modern method of gene therapy is employed, and the melanopsin is the human version rather than the mouse version. At this pace, the approach will be made obsolete by progress elsewhere in the field before any sort of clinical translation ever starts.

Even in end-stage retinal degeneration such as retinitis pigmentosa (RP), the remaining retinal layers and central visual projections remain structurally intact. Stimulation of these remaining cells is potentially sufficient to mimic visual responses and restore vision, and by this means the subretinal electronic implant has shown proof of principle for restoration of vision in patients after severe photoreceptor loss. An alternative gene therapy strategy involves the expression of transgenes encoding photosensitive proteins in remaining retinal cells, making them directly light sensitive in the absence of rods and cones.

A candidate protein for this purpose is melanopsin, the photopigment naturally present in a subset of ganglion cells that are intrinsically photosensitive - intrinsically photosensitive retinal ganglion cells (ipRGCs). Melanopsin is particularly suited to this purpose since it is native to the human eye and therefore is less likely to be immunogenic. Melanopsin shows greater sensitivity to light than alternative microbial optogenetic tools, such as channelrhodopsin-2 or halorhodopsin.

Previous work used intravitreal delivery of an adeno-associated viral (AAV) vector to express mouse melanopsin in ganglion cells with restoration of visual responses. We investigated whether human melanopsin could be effectively delivered via an alternative subretinal approach, using a ubiquitous (CBA) promoter to drive expression in all remaining outer retinal cells for several reasons. Subretinal vector delivery is well established in human clinical trials but has not been assessed in combination with a CBA promoter as an optogenetic approach for vision restoration. Transduction of cells in the upstream retina maximizes the potential of retaining complex processing of the visual signal. Furthermore, increased availability of chromophore in the outer retina may be required for effective photon capture in the absence of specialized outer segment discs. Other studies have used AAV vectors containing an enhancer to target a melanopsin-mGluR6 chimera or rhodopsin via intravitreal injection. However, there is variation in anatomy between primates and mouse models, and this may render the intravitreal approach less effective in humans. The increased risks of an inflammatory response following intravitreal AAV injection may also limit the translational potential of this route of delivery.

We therefore assessed transduction following subretinal delivery of melanopsin and whether this could support long-term restoration of light sensitivity and visual function in a mouse model of end-stage RP. Ectopically expressed melanopsin mediated depolarization of outer retinal cells and ultimately ganglion cell action potential firing, resulting in long-term restoration of the pupil light reflex and behavioral light avoidance up to at least 13 mo following injection. Finally, subretinal melanopsin expression led to light-induced changes in visual cortex blood flow and provided long-term improvements in a visually guided behavioral task that requires image-forming vision. In combination, these results suggest that this approach may be clinically useful in vision restoration in patients with end-stage RP.

Link: http://www.pnas.org/content/early/2017/09/26/1701589114.full

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