Back in our very first Vision Tech article, Four Emerging Vision-Enhancing Technologies, we introduced you to the Argus II artificial retina, developed by Second Sight Medical Products and approved by the FDA in February of 2013 for the treatment of late-stage retinitis pigmentosa (RP). The Argus II uses special eyeglasses with a mounted camera that streams video to a small receiver/computer. This unit encodes the stream and sends the information to a retina-implanted chip, which forwards the signal through tiny electrodes into the optic nerve, and from there to the visual cortex.
In our most recent Vision Tech article, Vision Technology in Clinical Trial Phase: New Approaches to AMD Treatment and Sight Restoration, from the December 2017 issue, we noted the company has now received permission to begin preliminary human clinical trials of a visual prosthesis known as Orion. Orion will use the same type of external glasses and processor as the Argus, but instead of sending the signal to a retinal chip, the signals will be delivered to the visual cortex directly.
Both of these devices require special glasses, an external power supply, and a processing unit.
But what if we could do away with at least two of these? That's the thinking behind a new implant currently in clinical trials from the German company, Retina Implant AG. The device, called the RETINA IMPLANT Alpha AMS is also an implanted microchip, but it works on a different principle than the Argus.
First, to review how the Argus works: the processing unit receives a video stream from the eyeglass camera, then processes and interpolates it. This digital signal is then streamed wirelessly to the retinal chip, which, in turn, stimulates a layer of specialized ganglion cells. These cells forward the electrical signals through the optic nerve to the brain, and viola—vision.
"The German thinking is that we could stimulate these ganglia cells using normal light that enters the eye, without an external processor," says Dr. Samantha De Silva, Honorary Clinical Research Associate at the Nuffield Department of Clinical Neurosciences at Oxford University. This research laboratory has collaborated with Retina Implant AG in clinical trials of the device. "Instead of lying atop the retina, the RI Alpha AMS chip is placed underneath. 1,600 photodiodes are activated by the light, which then stimulates remaining inner retinal cells, such as bipolar cells, along with any still-functioning rods and cones. These signals are passed along to the ganglia cells upon which they rest. Following the natural optical path, the signal is then transmitted to the brain via the optic nerve, with no need for glasses, no outside processing—just a small power supply the user wears behind an ear."
The surgery for implantation of the subretinal chip is complex, however, and De Silva is researching another, simpler way to restore vision in damaged retinas, one that will require a more routine operation.
"RP and other inherited retinal diseases are related to a progressive loss of photoreceptor cells, mostly the rods and cones," she notes. "Rods handle vision in low light, while cones specialize in color vision."
Each of these photoreceptor types uses special proteins, collectively called opsins, which are activated by light and produce a chemical signal. Rods use a protein called rhodopsin, while cones use a variety of opsins with varying sensitivity to red, green, and blue light waves. These chemical signals are forwarded to intermediate cells called bipolar and horizontal cells. Bipolar cells are so named because they accept input from both rods and cones. Horizontal cells are the cells that enable us to adjust vision to varying light levels. Both cell types convert these chemical signals into electrical impulses, which are, in turn, forwarded to the optic nerve.
"The retina also hosts a third, lesser known type of photoreceptive cell, which is a subtype of ganglion cell," says DeSilva. "They are not usually involved in active vision. Instead these are the receptors responsible for using light to help us to set our internal clocks."
The signals are subtle. Only about one percent of ganglion cells respond to light using its own photoreceptor protein, called melanopsin.
DeSilva and other researchers used gene therapy to create a modified virus that expresses melanopsin. They then injected the virus under the retina of mice with induced RP.
"A significant proportion of the bipolar and horizontal cells began expressing melanopsin in the area of the retina where the virus was injected," De Silva reports. "The mice began displaying pupil constriction with light, and their ability to detect a change in visual surroundings returned to that of the control group. And the cells continued to produce melanopsin for the lifetime of the animal."
Melanopsin cannot create color vision, only pixels of black and white. "We can't use either rhodopsin or one of the red, green, or blue color pigments because they require a complex series of reactions to become reabsorbed and regenerate," she says. "But we think with further work we can produce vision which is roughly equivalent to a retinal implant."
De Silva estimates it will take another three years to begin clinical trials. Meanwhile…
Inflammation and Retinal Disease
Also awaiting clinical trials is another retinal treatment being worked on by a team of researchers led by the Massachusetts Eye and Ear Infirmary at Harvard Medical School. These researchers are taking a step back in the AMD process, and looking at one likely regulator of the disease progression: inflammation.
"Lipids are major modulators of inflammation. Some are beneficial and others are deleterious," says team organizer Kip Connor, a vision scientist at Mass. Eye and Ear and Assistant Professor of Ophthalmology at Harvard Medical School. "Several types of lipids can suppress inflammation."
According to Connor, these bioactive lipids—organic molecules derived from fatty acids—can be divided into two broad categories: those that stimulate an immune response and those that dampen it. "In healthy tissue these two types are in relative balance," says Connor, "but due to injuries and other signals, they can get out of balance, leading to inflammation, which, in turn, causes the tissue to attempt to heal by producing—in the eye—more growth factors (e.g. VEGF)."
In preclinical studies Connor and others identified a class of lipids that are able to dampen the immune response, allowing for disease resolution. "We then added back these bioactive metabolites and found that they confer this protective effect by dampening the inflammatory potential of circulating immune cells," he explains.
The team has demonstrated a 40- to 50-percent reduction in disease severity in their preclinical models, but there is still considerable work ahead. "These compounds degrade very quickly in the body, so one of our challenges is finding ways to make them last," Connor explains. Currently, the team has isolated two active agents: 17,18-epoxyeicosatetraenoic acid (EEQ,), and 19,20-epoxydocosapentaenoic acid (EDP), both of which seem to confer protection.
Their German partners have found a way to create synthetic analogs of both compounds, which are not degraded and still confer protection. "These molecules show promising therapeutic potential not only for AMD, but also for other major conditions that involve angiogenesis and inflammation: atherosclerotic cardiovascular disease, diabetes (particularly diabetic retinopathy), cancer, and retinopathy of prematurity, to name a few."
Connor ends by noting: "Given the high prevalence and progressive nature of neovascular eye disease, the ability to stabilize bioactive lipids that mitigate or halt disease is of great and increasing therapeutic significance. It is our hope that emerging technologies and future studies will expand on our work and ultimately lead to safe, targeted, and cost-effective therapies that markedly improve visual outcomes and quality of life for patients suffering from these ocular diseases."
Related articles:
- Vision Tech: Earlier Diagnosis and Intervention Can Help Stanch Increasing Rates of Blindness by Bill Holton
- Vision Technology in Clinical Trial Phase: New Approaches to AMD Treatment and Sight Restoration by Bill Holton
More by this author:
