Partial Vision Restoration by Introducing Photoreceptor Functions into Retinal Neurons

This is the barnstorming era of biotechnology, in which researchers continually demonstrate new and interesting ways to re-engineer cellular biochemistry. Many of these initiatives are very intriguing and tackle issues of age-related dysfunction, but nonetheless probably won't lead to the development of therapies that make it to widespread clinical use. The example here is one of these, I think. Researchers have found a way to use a gene therapy to introduce some of the functionality of photoreceptor cells into the retinal neurons that lie behind the layer of photoreceptors, and have demonstrated the results in mice. The result is that in cases of blindness where near all normal photoreceptors are lost, the converted neurons take up some of the slack to send signals to the brain. Formerly blind mice given the treatment exhibit the ability to pick up changes in movement and shade in their surroundings.

Given that outcome, why do I think that this has only a modest future? A combination of a few factors. Firstly, it is quite early stage research, so one should expect it to take a decade or so for it to progress to the point at which someone is mounting clinical trials. Secondly it is a form of restructuring and compensation: it is not restoring original cell populations in the retina, but rather creating new hybrids and a new variant architecture of vision, a state of affairs that will introduce all sorts of complexities not present in straight regeneration. The combination of these two points means that this type of approach will, I think, lose out to forms of regenerative medicine capable of restoring the original population of photoreceptors and supporting tissue in the retina. That research is further along at this point and has more funding behind it.

(Further, assuming that we longevity advocates get our act together in the next decade or two all of these approaches will become unneeded for most people due to the advent of SENS therapies that periodically clear out the accumulations of metabolic waste that contribute to photoreceptor cell death).

This all said, partial restoration of visual ability via gene therapy would probably compete well with partial restoration of visual ability via electrode grid retinal implants, were they at the same level of clinical development. Both aim to add new architecture in order to push signals to the optic nerve, but are otherwise very different, with equally different potential paths towards improvement of quality. That path is known for electrode grids - add ever more electrodes to gain better resolution, and attempt to better mimic the effect of real photoreceptor signaling on retinal neurons - but improvement is an open question for gene therapy to convert neurons into photoreceptors. Still, gene therapy doesn't require surgery and a camera device in order to work, and avoiding surgery is always a big plus.

Restoration of Vision with Ectopic Expression of Human Rod Opsin

Inherited retinal degenerations (retinal dystrophies), such as retinitis pigmentosa, affect 1:2,500 people worldwide. Irrespective of etiology, most affect the outer retina and lead to progressive and permanent loss of photoreception. Severe visual impairment is common in advanced stages of the degeneration, and these conditions are currently incurable. However, despite the loss of outer retinal photoreceptors, inner retinal neurons, including bipolar and ganglion cells, can survive and retain their ability to send visual information to the brain. These neurons therefore, represent promising targets for emerging optogenetic therapies that aim to convert them into photoreceptors and recreate the photosensitivity that has been lost during degeneration.

Pioneering work has shown that electrophysiological responses to light can be restored to animal models of retinal degeneration by introducing a variety of optogenetic actuators to the surviving inner retina.These interventions can also support behavioral light responses including, in some cases, maze navigation or optokinetic reflexes reliant upon detection of spatial patterns or fast temporal modulations (flicker). However, in most cases, these actuators function only under very bright light, and, to date, no clinically achievable optogenetic intervention has recreated spatiotemporal discrimination at commonly encountered light levels.

Here, we set out to determine whether it is possible to recreate vision in blind mice using ectopic expression of a natural human protein, rod opsin. We expressed human rod opsin in surviving inner retinal neurons of a mouse model of aggressive retinal degeneration with near complete loss of rod and cone photoreceptors (rd1) by intravitreal administration of clinically approved adeno-associated virus (AAV) vector, AAV2/2. Widespread light-evoked changes in firing were observed in neurons of the retina and dorsal lateral geniculate nucleus (dLGN) in treated mice. These responses could be elicited using physiologically encountered light levels and under natural light-adapted conditions. Behavioral studies indicated that the treated mice had regained the ability to detect modest changes in brightness, relatively fast flickers, spatial patterns, and naturalistic movie scenes.


How is this different to Gensight's GS030 optogentics clinical trial candidate?

"Our second product candidate, GS030, is based on optogenetics, a technology that makes cells responsive to light by using a viral vector (an engineered AAV2) to introduce a DNA sequence that encodes a photosensitive protein belonging to channelrhodposin (ChR) family, into the nucleus of the target cells. Once this protein is expressed, it confers a photoreceptor-like function to the target cell, hence enabling restoration of vision in patients with extremely reduced vision or total blindness due to RP."

Posted by: Jim at August 13th, 2015 8:31 PM

@Jim: Hah, exactly the same by the look of it, just a different protein. I hadn't given enough attention to Gensight's other work, clearly. Ok, so perhaps this line of research is further along than I thought it was, and so the role of competitor to electrode arrays is more apt.

Posted by: Reason at August 13th, 2015 8:39 PM

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