Week in Review: Number 14

Models for Precision & Color in Argus II Retinal Implant
The present pair of studies explored improvements to the Argus II retinal implant using electrical simulation wavefront models for greater precision of target stimulation as well as the encoding of basic color. The Argus II retinal prosthesis uses a camera mounted on special glasses to detect patterns of light. These signals are then relayed to an array of 60 electrodes that stimulate retinal ganglion cells (RGCs). The implant is used in patients whose photoreceptors no longer detect light, such as in severe cases of retinitis pigmentosa, by stimulating retinal ganglion cells downstream of the photoreceptors. The axons of retinal ganglion cells together form the optic nerve that relay the signal to the brain for visual perception. In some patients, off-target stimulation of the axons rather than the cell body results in the perception of elongated phosphenes rather than the intended dots of light. To address this issue, the researchers used a computer model of two types of retinal ganglion cells, D1-bistratified and A2-monostratified, at the single-cell level and in large networks. They identified a pattern of short pulses that preferentially targets the cell bodies with less off-target activation of axons. In a more recent study, the same team of researchers applied the same computer models to study the encoding of color by retinal ganglion cells. Prior tests in patients revealed that the perception of color depended on the frequency of electrical stimulation. The second study uses computer models to predict eliciting color perception, specifically by stimulating small bistratified cells that contribute to blue-yellow color opponency, i.e., blue and yellow color perception. These two studies provide information to guide improvements in the Argus II retinal prosthesis toward more precise and colorful visual perception for the blind.

Citicoline Supplementation as Neuroprotection Independent of IOP in a Rat Model of Glaucoma
Citicoline is a major source of choline, a building block of cell membranes, including those of the nerve cells that transmit information from the eye to the brain. The authors note that previous studies in humans and rodent models of glaucoma showed lower levels of choline in the brain, but there has been little research into the effectiveness of choline supplementation as a glaucoma therapy. The present study in rats found that ingesting citicoline restored optic nerve signals between the eye and the brain independent of intraocular pressure (IOP). As such, citicoline is of particular interest as a novel mechanism for the treatment of glaucoma. In the vast majority of cases, elevated eye pressure is a risk factor for damage to the optic nerve, resulting in glaucoma. However, many studies have shown that glaucoma progression continues despite good eye pressure control, suggesting additional mechanisms of the disease. Despite hints of alternative mechanisms, contributing to normal tension glaucoma, for example, eye pressure has been the only variable that can be modified clinically. Neural protection and reversal of optic nerve damage are the holy grails of glaucoma research. The fact that citicholine can reduce vision loss in mice independent of eye pressure is intriguing. In particular, the research team induced glaucoma in several dozen rats using a clear gel. For rats with mildly elevated IOP, optic nerve and other tissues decayed for up to five weeks after injury. In rats treated with oral doses of citicoline over a three-week period, nerve degradation was reduced by 74%, suggesting a neuroprotective effect. Furthermore, reduced vision loss was sustained for another three weeks after treatment was stopped. The researchers caution that there are several steps between lab research and commercial development of an effective drug. They next intend to further investigate the connection between choline and neural protection.

Txnip Gene Therapy for Three Types of RP in Mice
Retinitis pigmentosa (RP) is a genetic eye condition that results in progressive dysfunction or loss of the photoreceptors in the retina, beginning with loss of rod photoreceptors and later also affecting cone photoreceptors. Currently, more than 100 gene loci for retinitis pigmentosa have been mapped or identified. However, targeted gene therapies have only been able to treat specific gene defects rather than wider sets or families of the disease. As the lead author states, “A gene therapy that would preserve photoreceptors in people with retinitis pigmentosa regardless of their specific genetic mutation would help many more patients.” To find a gene-agnostic therapy that could apply more broadly, the researchers screened 20 potential therapies in mouse models of RP, selecting for therapies that target sugar metabolism based on the theory that cone photoreceptor degeneration in RP was due to loss of glucose supply. Their experiments found that a gene called Txnip, especially an allele called C247S, was most effective in treating RP across three different mouse models. C247S in particular helped the cone photoreceptors switch to alternative sources of energy and improved mitochondrial health. Additionally, the rescue effect of Txnip depends on lactate dehydrogenase b (Ldhb), suggesting that this therapy improves cone photoreceptor health by enhancing lactate catabolism. Combining Txnip gene therapy with additional gene therapies that reduced oxidative stress and inflammation provided additional cellular protection. The researchers intend to further their studies in animal models beyond mice before starting clinical trials in humans.

Microgravity Manufacturing of Artificial Retina
Industry researchers are exploring the development of an artificial retina using bacteriorhodopsin, with intended manufacturing in the microgravity environment of space on the International Space Station. A representative for one of the companies explains, “When gravity is nearly eliminated, so too are forces such as surface tension, sedimentation, convection driven buoyancy, all of which can interfere with the orientation and alignment important in the creation of crystalline structures, nanoparticles, or improved uniformity in layering processes." Similar to rhodopsin in human photoreceptors, bacteriorhodopsin is a light-sensing protein found in extremomophile microorganisms of the Archaea domain of life. When activated by light, bacteriorhodopsin pumps hydrogen ions across a membrane, generating an ion gradient. Additionally, bacteriorhodopsin's molecular structure is highly ordered and thermally stable for nanotechnology applications. In the artificial retina, layers of purified bacteriorhodopsin generate an ion gradient across a permeable membrane, acting in place of photoreceptors, to stimulate bipolar cells and retinal ganglion cells. From there, the signal is relayed via the optic nerve to the brain as usual. The microgravity environment of space facilitates layering the bacteriorhodopsin in a more precise orientation to create a unidirectional ion gradient, which the companies anticipate would persist when returned to gravity on Earth. The companies are working toward FDA approval for the use of their artificial retina for retinitis pigmentosa, with preclinical data still underway prior to clinical trials.

Complement Factor H in C. Elegans Model of AMD
Researchers working with a laboratory model of C. elegans have found a potential new mechanism for age-related macular degeneration (AMD). Specifically, they looked at the contribution of protein complement factor H (CFH), after previous research showed that mutations related to it are seen in a large number of AMD patients. The role of complement factor H is to mark cells in the body as self to protect them from an immune attack. This link between CFH and AMD led some researchers to hypothesize that AMD is due to the immune system attacking the body's cells that were not marked as self. The researchers were curious to explore new mechanisms of the disease using nematode lab models. Roundworms have a version of CFH in the middle of their antennas, specifically in the cilia, which are responsible for sensing the environment. The CFH proteins are located next to another important antenna protein called inversin. In roundworms bred to lack CFH, inversin is spread throughout the antennas rather than located in the middle. Roundworm antennas have some structural similarities to the photoreceptors of the human eye. For example, CFH and inversin have the same positioning in the cilia of photoreceptors in healthy human retinal tissue. However, in people with CFH mutations, inversin was spread around rather than located in neat bands. The authors state, "The role of CFH in cilia compartment boundaries is conserved in vertebrate photoreceptors, suggesting that structural defects in photoreceptor cilia make a contribution to AMD progression in patients with CFH mutations that has not been appreciated previously."

In Other News
(1) Evolution of the eye-brain connection
(2) Adverum patient loses sight in eye treated with gene therapy
(3) A veterinarian explains comparative eye anatomy: owl eyes