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In the back of the eye stands a far outpost of brain tissue. Here, photosensitive neurons of the retina transform light into nerve signals that a few synapses later will become images that enable us to navigate and appreciate our world.
Among the ills this crucial bit of central nervous system (CNS) is heir to is a leading cause of severe vision loss: age-related macular degeneration (AMD). An estimated 2 million people in the US—nearly 2 percent of those over age 50—suffer from this disorder, in which photoreceptors in the central, most sensitive part of the retina die off, making it progressively difficult to read, drive, or enjoy movies or TV.
Monthly injections into the eye can sometimes halt the aggressive “wet” form of AMD, that makes up just 10 percent of cases. Nothing can stop the advance of far more common “dry” AMD (although a mix of nutritional supplements can reduce the risk of progression in 25 percent of those whose vision is still largely intact.)
But there’s hope on the horizon. Stem cells, derived from embryonic or genetically engineered adult tissue, can be induced to differentiate into specialized cells to replace those lost to trauma or disease. The idea has obvious appeal for treating CNS disorders including Parkinson’s and Alzheimer’s disease, but nowhere has exploration gone further than in the retina. [Exploration, not treatment: please see caveat at end of story.]
Research has, for the most part, focused not on photoreceptors but on the retinal pigment epithelium (RPE) cells that support them. RPE cells ferry nutrients to the photoreceptors, remove waste tissue, and recycle pigments vital for their function. They die first in AMD, and photoreceptors die for want of them.
“RPE cells can survive without photoreceptors, but photoreceptors can’t survive without RPE cells,” says Kapil Bharti, head of the unit on ocular stem cell & translational research at the National Eye Institute. “That’s why we have to make RPE cells first.”
There are practical reasons, too. “Integrating implanted photoreceptors with the host retina would be very challenging” because they must connect via synapses with other neurons, says Marco Zarbin, professor and chair of ophthalmology and visual science at New Jersey Medical School and co-editor of a book, Cell-Based Therapy for Degenerative Retinal Disease (Humana Press. 2019). “RPE cells integrate very [simply]; they don’t make synapses.”
While implanted RPE cells can’t bring dead photoreceptors back to life, “we can hope at least to stabilize vision, and perhaps to bring about some degree of improvement,” he says. “Some photoreceptors are dying—no longer functioning but not dead yet. RPE cells produce nerve trophic factors; if we transplant them nearby, some photoreceptors could start to function again.”
Early results from phase 1 clinical trials suggest that this is not an impossible dream. One study, conducted by the London Project to Cure Blindness at University College, London, has thus far included two people with wet, or exudative AMD—an advanced stage of the disease in which new blood vessels develop and leak, swiftly killing retinal cells.
“We took patients with very bad bleeds that injection therapy was not able to stop,” says Peter Coffey, director of the London Project and senior author of the Nature Biotechnology paper reporting the research.
His research team implanted a patch of RPE cells derived from embryonic stem cells (ESCs) and grown on a synthetic matrix. Twelve months later, microscopic examination confirmed that the implants had survived. What was more, the patients’ vision had improved markedly. The first patient could read 86 words per minute after the procedure, compared to 1.7 words earlier.
Improvement for the second patient, an 86-year-old man whose vision was “really dreadful,” was even more dramatic. “I was gob-smacked,” says Coffey. “Before the implant, he couldn’t see the book, now he could read at 50 words per minute.”
The patients have maintained their gains three years after surgery, he says.
Impressive as these results are, they may not mean exactly what they seem, says Zarbin. In wet AMD, “just removing abnormal blood vessels without a transplant, one-fourth of patients will get [significant] improvement. That the transplant had a beneficial effect isn’t an outrageous claim, but it’s not clear-cut.”
In another recent study, the efficacy of the implant was “absolutely clear-cut,” he says. These preliminary results, reported in Science Translational Medicine, involved four patients with geographic atrophy, the advanced form of dry AMD in which both RPE cells and photoreceptors in regions of the retina are irretrievably lost. They were given a patch of ESC-derived RPE cells on a synthetic matrix meant to simulate the underlying membrane.
“Since it was a phase 1 trial [whose principal aim is demonstrating safety], we were obligated to treat end-stage disease,” says Amir Kashani of University of Southern California, first author of the paper. “We didn’t expect that replacing RPE cells would return a significant amount of vision.”
In one of the four patients, however, acuity substantially improved. Acuity remained stable in the others, while their ability to focus on a fixed object–another measure of retinal function lost to the disease—returned.
The fact of these improvements “means that maybe we don’t understand how much potential is left, and we could be warranted to try treatment at a later stage [of AMD] than we think,” Kashani says.
ESC-derived implants like those in the above studies require patients to take immune-suppressant drugs indefinitely, to prevent rejection. Such drugs can be troublesome over the long term, particularly for older patients.
No immune suppressants would be needed, however, with an implant based on stem cells derived from a patient’s own tissues—autologous induced pluripotent stem cells, or iPSCs.
Using an animal model of retinal degeneration, researchers at the National Eye Institute found that an implant made from human iPSC-derived RPEs continued to function and was integrated into the retina. “We hoped that the patch would protect photoreceptors from dying, and it did,” says Kapil Bharti, who led the research team. Potentially malignant genetic instability—a worry with iPSCs—failed to appear.
“This proof-of-principle study gives us more confidence for doing human patient surgery,” says Bharti. If their application to the FDA is approved, the researchers hope to begin a phase 1 clinical trial later this year.
If the two ongoing clinical studies cited above continue to have positive results, the next step would be larger trials with patients who have less advanced disease—and more vision to preserve.
Should these and following trials be successful, and grafts approved for clinical use—five years is an optimistic prediction—likely beneficiaries would be patients in whom AMD has progressed to the point that such an ambitious intervention is indicated, but whose vision is largely intact. “There is a sweet spot—an identifiable stage when some RPE cells have been lost, but the impact on photoreceptors is still minimal,” Kashani says.
Even if clinical trials lead federal regulatory agencies to give implants the go-ahead, questions of cost will remain, particularly with autonomous grafts, where a new cell line must be developed for each patient.
“We believe economic barriers can be surmounted using forms of automated production,” says Lisa Strovink, chief strategy officer at the New York Stem Cell Foundation, where an autonomous implant project is just getting under way. “We’ve developed systems for research-grade stem cells that remove all human interactions, and believe we can apply them in modified format” for clinical use.
The implications of a clinically adaptable retinal implant would go far beyond the retina. “This would be the first application of stem-cell based therapy to neural tissue,” says Zarbin. “My abiding suspicion is that the principles we figure out for treating the eye will hold true elsewhere in the CNS… for Alzheimer’s, Parkinson’s, stroke, traumatic brain injury.”
[A caveat: The exciting prospect of stem cell-based therapy for AMD is still just that: a prospect. Don’t confuse the incremental steps of these tightly-controlled studies with the unproven and unapproved treatments offered by dubious “stem cell clinics” that have proliferated across the country—over 500 at one count. These facilities derive stem cells from patients’ fat, and inject them into various body parts to treat a smorgasbord of medical issues—including AMD.
The results can be catastrophic. In three cases, reported in the New England Journal of Medicine, patients with AMD lost their vision altogether after treatment.]