September 2020


Gene Therapy
Stem cell replacement therapies for the eye

by Liz Hillman Editorial Co-Director

A magnified portion of lab-grown, human induced pluripotent stem cell (iPSC)-derived retinal organoid immunostained for cone (yellow) and rod (red) photoreceptors
Source: Dr. Beth Capowski, Gamm Lab

Stem cells are cultivated from a healthy limbal biopsy, grown on an amniotic membrane scaffold, and transplanted to the limbal stem cell deficient eye.
Source: Ula Jurkunas, MD

Researchers will take a patient’s own blood cells and in a lab, convert them into iPS cells capable of becoming almost any type of cell in the body. In this case, the iPS cells are then programmed to become retinal pigment epithelial cells, the type of cell that dies early in the geographic atrophy form of AMD.
Source: National Eye Institute

“I think we are at the beginning of [stem cell therapy for the eye] because there is so much more that we can do.”
—Ula Jurkunas, MD


Stem cell-derived therapy is an attractive treatment option in situations when there is not necessarily a genetic component to the disease to correct (though there could be) and/or if the cells are not healthy enough for a gene therapy to correct a condition. A few options are currently in clinical trials for ocular disorders.
“Replacement cell therapy using stem cells is aimed at later stages of disease when cells are terminally damaged or dead, in which case gene therapy would not work,” said David Gamm, MD, PhD.
In the eye, stem cell therapy has been in the works for more than 2 decades, with Pellegrini et al. describing transplant of cultivated limbal stem cells for limbal stem cell deficiency (LSCD) in 1997.1 While such stem cell therapies have been available to patients in Europe and Asia, they are still in clinical trial stages in the U.S.
Ula Jurkunas, MD, described research for cultivated limbal stem cells as the first stem cell trial funded by the National Eye Institute (NEI) for the cornea.
“The way it works, in general, is you take a small biopsy from the healthy eye of the limbus. Expand the cells with various techniques in the laboratory. … After growing them and making more of those cells, you take them back to the surgeon—it takes about 2 weeks for the cells to grow—and transplant them on an unhealthy eye, the eye that has limbal stem cell deficiency,” Dr. Jurkunas said, noting that the cells they are cultivating in the U.S. clinical trial are with good manufacturing practice (GMP) products. “This isn’t new; it was first described in 1997. It just took a while to develop consistent manufacturing using qualified and validated reagents and make them into the FDA-ready product here in the U.S.”
Dr. Jurkunas explained how stem cell therapy for LSCD might be advantageous over other techniques. Unlike corneal limbal allografts, which require systemic drugs to reduce chance of rejection, limbal stem cells come from the patient’s own tissue and thus won’t elicit an immune response.
Another treatment option is to take two larger biopsies from the other eye, if it’s healthy, but this, Dr. Jurkunas said, puts the other eye at risk for stem cell deficiency.
“With [cultivated stem cell therapy] we can take a small biopsy, 2 mm as opposed to two 4 mm biopsies; that makes it safer and helps a bigger population. A lot of times people have asymmetry, some stem cell deficiency in their ‘good’ eye, and they might not have the ability to take those big biopsies,” she said.
Simple limbal epithelial transplantation (SLET), which also involves taking a small biopsy and transplanting small pieces of this stem cell tissue onto the LSCD eye, doesn’t always work, Dr. Jurkunas said.
“I am a big believer that SLET works in milder cases, but in more severe cases it is a little hard for it to work,” she said.
Once FDA approved, Dr. Jurkunas envisioned that any cornea specialist would have the skills to take the limbal biopsy and transplant the sheet of expanded, cultivated stem cells back onto the cornea.
“I think we are at the beginning of [stem cell therapy for the eye] because there is so much more that we can do. For example, I think the future is we might take the limbal biopsy, grow the cells, and genetically modify these cells … before we transplant them,” Dr. Jurkunas said.
In December 2019, NEI launched its first clinical trial for stem cell-derived therapy for advanced dry age-related macular degeneration. The historical basis for this research, Kapil Bharti, PhD, said, is a procedure where a piece of healthy retinal pigment epithelium (RPE) is cut and transplanted to the degenerated area of the macula. This procedure was complicated and often failed, but there were a small number of cases where vision was restored.
“For me this was a founding principle, that if we were to make an autologous RPE patch from a macular degeneration patient and from their own stem cell and bring it to the right place, we have a chance at making a therapy,” Dr. Bharti said.
In animal models, a transplanted patch of RPE cells, derived from stem cells, was evaluated with OCT, measurement of electrical response of the retina, and histology after the animal was euthanized. Dr. Bharti said they saw an electrical response in the area of the retina that had an RPE patch transplanted after laser ablation damage vs. an empty scaffold in a laser ablated area that did not see a response.
“That gave us more confidence that it’s not only preserving photoreceptors that we see by OCT or histology, it’s preserving the synaptic connections of the photoreceptors to the retinal neurons and the visual processing is happening,” Dr. Bharti said, adding that the research team has been refining its techniques and recently obtained an instrument that can look at a single cone photoreceptor at a time, assessing whether it’s being preserved over the transplant.
In the first-in-human clinical trial, Dr. Bharti said the RPE patch is being transplanted in the transition zone, between the area of the lesion and where there is still healthy retina in the hope of preventing additional photoreceptors from dying.
“Once we demonstrate the safety of this procedure, we hope we can transplant at an earlier stage with most of the photoreceptors still viable,” he said.
Even further in the future, Dr. Bharti said they hope to test similar stem cell therapy for situations where the photoreceptor cells are no longer viable, such as in advanced retinitis pigmentosa or cases of eye injuries.
Elliott Sohn, MD, is on a team working toward a stem cell therapy that could restore vision after cell loss. While gene therapy is useful, in general, for earlier stages of disease, in advanced stages where photoreceptors and potentially surrounding cells are degenerated and/or dysfunctional, stem cell therapies will be a primary way to restore vision, he said.
“The stem cell work that we’re doing is focused on trying to recreate a patient’s own photoreceptors made from their skin cells to restore vision, after we genetically correct the cells of their mutation before they get them,” Dr. Sohn said. “To achieve this we take a skin sample from the patient, bring it to the lab, turn them into induced pluripotent stem cells (IPS), correct the genetic mutation in these cells, then, because they’re stem cells, we would turn them into the patient’s photoreceptor cells; they could then be put into a scaffold that is inserted under the retina to integrate with the retina in place of the patient’s degenerated photoreceptor cells.”
At this point, Dr. Sohn said the visual pathways in the brain would need to already be developed for this treatment.
“It may be possible if a baby was missing photoreceptors that stem cell-based photoreceptor treatment could help restore those pathways to help them to see, but that would be something to investigate further down the road vs. starting with someone who is totally blind and already had vision when they were young,” Dr. Sohn said.
At this point, Dr. Sohn said this research is at a laboratory stage with testing being done on small and large animals. His advice, in general, for ophthalmologists is if they have a patient with an inherited retinal condition to send them to an experienced inherited eye disease specialist; there might be a clinical trial for a treatment in progress or coming soon.

At a glance

• Stem cell-derived therapies for corneal and retinal conditions are in clinical trials in the U.S.
• A replacement cell therapy using stem cell-derived eye tissues could be useful when the patient’s own eye cells are damaged or dead.
• Researchers are looking at cultivated stem cells for limbal stem cell deficiency as well as replacement photoreceptor cells for transplant for retinal conditions like retinitis pigmentosa and dry AMD.

About the sources

Kapil Bharti, PhD
Senior investigator
Ocular and Stem Cell
Translational Research Section
National Eye Institute
Bethesda, Maryland

David Gamm, MD, PhD
RRF Emmett A. Humble
Distinguished Director
McPherson Eye Research Institute
University of Wisconsin
Madison, Wisconsin

Ula Jurkunas, MD
Associate professor
Department of Ophthalmology
Harvard Medical School
Boston, Massachusetts

Elliott Sohn, MD
Associate professor
of ophthalmology and
visual sciences
University of Iowa
Iowa City, Iowa

1. Pellegrini G, et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet. 1997;349:990–993.

Relevant disclosures
: None
Gamm: None
Jurkunas: None
Sohn: None



Cautioning patients about stem cell scams

David Gamm, MD, PhD, writes in a document for his patients that the hope for stem cell technology is real, however, there is a “difference between hope and hype.” Dr. Gamm warns patients about clinics offering “miracle cures” that could actually cause physical and/or financial harm.
He notes that almost all stem cell therapies are still in clinical trial or laboratory stages and, thus, patients should be skeptical of stem cell therapies that require a fee or claim to be a “cure-all.” In his document, which he gave EyeWorld permission to cite, Dr. Gamm writes that ethical scientists engaging in clinical trials enroll patients “without asking for, or accepting, payment (often, they pay YOU).”
To avoid scams, Dr. Gamm explains what the retina is and the types of disorders that can affect its function. He tells patients that most of these disorders do not have a cure or treatment available yet, which is why there is research looking at turning stem cells into retinal cells and transplanting them.
“There is no magic to stem cells, but there is a great deal of excellent, well-designed, and well-intentioned research being performed in the stem cell field,” Dr. Gamm writes. “Stem cells have unique but variable properties that, if thoughtfully tested and applied, may be of considerable help to some patients in the foreseeable future. We’re optimistic about this future … and you should be, too.”

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