By Gerald J. Chader, PhD

Retinal degenerative diseases affect millions of Americans and similar numbers of people in Europe. It is estimated that 30 million people are affected worldwide. Although some treatments for these conditions are available, or are being planned, they are dependent on the integrity of the retinal photoreceptor layer, the cell type most vulnerable in retinal degenerative diseases.

What is available to patients whose photoreceptor cells die, as in the later stages of these diseases or in aggressive, early onset retinal degenerations? The answer may lie in tiny electronic devices implanted on the neural retina.

The Need

To date, there is no effective treatment for the millions of patients with dry AMD, or for those with retinitis pigmentosa and allied diseases. Although the number of patients with RP is lower than those with AMD, RP can cause marked vision loss or blindness even from birth. This can create a severe socioeconomic burden for individuals as well as society for the lifetime of otherwise healthy people. A retinal prosthetic device ("chip") affords the best possible opportunity to at least partially restore functional vision for the widest number of patients with moderate to severe vision impairment caused by retinal degeneration.

Multiple Approaches to Chip Development and Placement

In simple terms, the chip can functionally take the place of dying or dead photoreceptor cells. To achieve this, groups around the world are taking different approaches with regard to the type of device used and its placement. Devices that abut the optic nerve and ones that provide suprachoroidal-transretinal stimulation are being studied.

Another novel approach involves the directed migration of secondary retinal neurons into spaces or pores of the implanted chip, potentially allowing for closer and more specific interaction. Bypassing the eye completely is the aim of those developing cortical devices. However, the two approaches that are farthest along in development are subretinal and epiretinal implants.

The subretinal approach, in which the device is placed between the RPE cells and the remaining retinal layers, has the advantage of the chip being placed in a "photoreceptor" position such that it has the potential to interact with natural target neurons of photoreceptors like bipolar cells, etc. However, surgery is fairly disruptive.

In the epiretinal approach, the device is placed on the vitreal surface of the retina. This is less disruptive and provides more flexibility in component placement. However, the target neurons are less well defined, and it appears that more complex stimulus algorithms are needed.

Subretinal Implants

The basic chip designed by Drs. Alan and Vincent Chow of the Optobionics Company is perhaps the archetype of the subretinal devices and is farthest along the clinical pathway. This passive device, the Artificial Silicone Retina (ASR), is composed of tiny solar cells that, when activated by light, will theoretically send an electrical signal through the secondary neurons of the retina (e.g., bipolar cells, etc.) and down the optic nerve to the brain. A potential problem with such passive devices is that they may generate too little power to be effective. Most other chip designs have devices that increase the output power at the retina level.

In spite of this potentially serious problem, the Optobionics device has been in FDA-approved clinical testing for about five years. Importantly, safety issues seem to be well in hand since the retina tolerates the implant well. Vice versa, the chip seems to tolerate the hostile environment of the subretinal space, although more work on this issue needs to be done.

To the surprise of many, several of the patients chosen for the initial Safety Phase 1 part of the trial reported improved vision. This was mainly "subjective" improvement in areas such as brightness, contrast, visual field and color discrimination. Subsequently, Optobionics has made great strides in developing more objective methods of testing and has confirmed the early improvement. In the last two years though, a decline in vision has been found in many of the patients. Also, an odd phenomenon was noted. Essentially, the visual improvement encompassed a considerably larger area than that subserved by the tiny chip itself -- i.e., there was visual improvement in retinal areas relatively far from the device.

A series of collaborative research efforts in test animals using active and inactive devices has led to the conclusion that chip implantation probably induces the secretion of natural neurotrophic factors by retinal cells that could lead to both prolonged life of retinal neurons and improved function.

Dr. Chow postulates, "Persistent improvements in visual function in the retina both adjacent to and distant from the ASR implant continue to suggest a neurotrophic benefit of the chip..." This "injury-response" mechanism is reminiscent of retinal transplantation experiments in the 1980s, when sham-operated retinas in test animals had "improved" visual responses comparable to those receiving actual photoreceptor transplants.

Currently, Optobionics is continuing its clinical investigations as well as further examining the possible neurotrophic effect of the chip.

Epiretinal Implants

Among the several epiretinal efforts, that of the consortium of investigators led by Drs. Mark Humayun and James Weiland at the University of Southern California and the Second Sight Company is farthest along in clinical testing. These investigators have impressive collaboration and support from the NSF, along with the US Department of Energy and five of its National Research Laboratories. As conceived by this group of investigators, the epiretinal chip is much more complex than the Optobionics chip. A small video camera will be hidden behind a pair of glasses worn by the patient to initially capture the visual image. These images will be relayed to a small computer worn on a belt, then to an antenna behind the ear, which will finally send the signal to the epiretinal implant within the eye. Currently, this implant has 16 individual electrodes that can interact with retinal neurons, but 32 arrays and higher are being tested for future implantation. In this design, the electrical signal is greatly amplified to within the range thought to be recognized by the retina.

So far, the epiretinal team has implanted six devices in patients and, as with Optobionics, has found the devices to be relatively safe. Also as with the subretinal implants, some efficacy has been reported -- again, surprisingly, since the initial patients chosen had very poor vision, befitting the Phase 1 Safety part of a Clinical Trial. Shape, spatial and motion discrimination were improved in several patients, some of whom had no functional vision prior to the beginning of the trial.

This epiretinal effort is currently continuing with high expectations for success. Implantation of devices with large numbers of electrodes is certainly possible, theoretically allowing for a better visual image.

Chip Challenges

So what still remains to be done? In the current and proposed clinical trials, there is a need to prove long-term safety for both the human subject and the electronic implant. Also, efficacy has to be demonstrated conclusively -- efficacy that hopefully lasts for years, if not for the lifetime of the patient. Testing procedures need to be improved. Psychophysical tests need refining, as well as the application of tests such as OCT and electrophysiological recordings from the retina and brain that demonstrate not only "vision" at the retinal level but also in cognitive centers that yield functional results.

An important problem that ultimately might limit the usefulness of the chip (even if it does prove to work in future) is the phenomenon of "retinal reorganization." It is well known that retinas affected with an inherited degeneration sustain damage in the inner retinal layers (bipolar, ganglion, etc., cells) as well as lose photoreceptor cells. Some inner retinal neurons die (up to 70 percent of ganglion cells in some eyes with RP) and others "remodel," sending out axonal-like processes (neurites) in areas of heavy photoreceptor loss. These and other abnormalities have been cataloged by the work of Drs. Ann Milam, Mark Humayun and, more recently, the elegant work of Dr. Robert Mark. The neuritic sprouts become associated with surfaces of inappropriate secondary neurons and glia, and may simply be searching for stimulatory input and contact. This could then contribute to the ERG abnormalities seen in RP patients and speed their progressive decline in vision. Due to CNS neuronal plasticity, however, it very well may be that some of these abnormal effects could be reversed after the imposition of a more normal electrical input from the chip.

Whether the chip (subretinal or epiretinal) works is the critical question, but an intriguing corollary is whether neurotrophic factors induced by chip implantation (surgery and/or electrical stimulation) play a role in visual "improvement" in implanted patients. In the case of the Optobionics device, this does seem to be the case. Thus, supplying exogenous neurotrophic agents at the time of implantation may enhance both the acute and chronic results.

Conclusions

Chip implantation may be the final hope for patients with retinal degenerations in which the disease has progressed to a point where most or all of the photoreceptors are gone and the more conventional therapies (gene therapy, pharmaceutical therapy) are not applicable. Although there are areas of chip development that still need more work-- the electronics, the biological interface, brain recognition, etc. -- significant progress has been made, as attested to by the two current clinical trials in progress and the many groups around the world working on different chip model systems.

Thus, the future of the chip looks bright not only for low-grade mobility for patients but also in enhancing face recognition and reading ability. In the final analysis, the cost for development of the chip is substantial, but who can put a price tag on restoring a person's sight?

Gerald J. Chader, PhD, is the Chief Scientific Officer, Doheny Retinal Institute at USC Medical School.

Source: Lighthouse International's Aging & Vision newsletter

 

 

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