NEW ORLEANS — Retinal pigment epithelial (RPE) cells derived from human embryonic stem cells can be safely transplanted into the eyes of patients with retinal degeneration, with early signs of vision gain, according to pioneers in the field.

Two teams of researchers reported preliminary findings from phase 1 and phase 2 trials at the American Academy of Ophthalmology (AAO) 2017 Annual Meeting. Patients had the dry form of age-related macular degeneration (AMD) or Stargardt disease and received injections of human embryonic stem-cell (hESC)-derived RPE cells.

At a press briefing, the presenting authors were optimistic but cautious, as the studies are very early and very small. "We are encouraged by the results thus far," said Eyal Banin, MD, PhD, from Hadassah-Hebrew University Medical Center in Jerusalem, Israel. "But this is just a first step in the long road towards making regenerative cell therapy a reality in macular and retinal degeneration."

While some patients in her study have gained vision, Ninel Z. Gregori, MD, from Bascom Palmer Eye Institute, Miami, Florida, said, "These trials show long term safety and possible biologic activity of pluripotent stem-cell derived progeny, but they were not powered to show efficacy."

Replacing Failing Cells

Dysfunction and degeneration of RPE cells contribute to vision loss in AMD. In both studies presented here, human embryonic stem cells were turned into RPE cells and injected into the subretinal space of patients with retinal degeneration at a dose of 50,000 to 200,000 cells. The expectation is that, once in place, the new RPE cells will support or replace the patient's own failing RPE cells and boost the survival of photoreceptors.

Human embryonic stem cells have an endless capacity to divide, offer an unlimited source of cells, are capable of becoming any type of cell, and can be differentiated in the laboratory. The use of hESC-derived cells is an attractive treatment approach, in fact, for many different diseases because transplanted cells may be able to react to changing conditions in the microenvironment, which is an important biological process, Dr Banin pointed out.

Dr Gregori and her multi-institutional team conducted two phase 1/2 trials using hESC-derived RPE cells, one in dry AMD patients (n = 13) and the other in Stargardt disease (n = 13). The 20 patients with poor visual acuity (≤ 20/400) received 50,000 to 200,000 RPE cells, and the six patients with better vision (≤ 20/100) received 100,000 cells. A 13-week regimen of systemic immunosuppression was initiated 1 week before transplantation.

At a median follow-up of 4 years, the researchers have seen no safety signals related to transplantation of RPE cells. There have been no cases of tumor formation, vitritis, macular edema, secondary glaucoma, retinal detachment, adverse preretinal RPE cell engraftment, vascular occlusion, photophobia, or obvious rejection.

A number of common or serious ocular events have been seen, but are considered related to the surgical procedure and not the transplanted cells. There were also some nonocular conditions attributed to the immunosuppressive medications and to underlying health status.

Of the 26 patients, 24 (92%) developed areas of subretinal pigmentation that did not correlate with cell dose or visual acuity outcomes. Fundus autofluorescence changes were variable. Six patients demonstrated preretinal pigmented cells near the site of injection. Two had epiretinal membrane formation that was noncontractile.

"These trials were not designed for efficacy and there's no control group, so you have to take this with a grain of salt — but there was increased visual improvement in the treated eye," Dr Gregori reported.

The table shows the 12-month and 24-month best-corrected visual acuity (BCVA) response (10+ letter increase) for 18 patients with AMD and Stargardt disease in the treated and untreated eyes (Table).

Table. BCVA Response with Treatment

BCVA Response ≥ 10-Letter Increase Advanced AMD (N = 9) Advanced Stargardt Disease (N = 9) Month 12 Month 24 Month 12 Month 24 Treated Eye Untreated Eye Treated Eye Untreated Eye Treated Eye Untreated Eye Treated Eye Untreated Eye 4 (44.4%) 2 (22.2%) 3 (33.3%) 1 (11.1%) 4 (44.4%) 1 (11.1%) 3 (33.3%) 1 (11.1%)

BCVA = best-corrected visual acuity

Dr Gregori described one patient with dry AMD whose study eye improved by 19 letters at 24 months, ultimately reaching 38 letters, up from 19 at baseline. Her baseline visual acuity was 20/500, improving to 20/200. In the untreated eye, she lost two letters and visual acuity remained the same.

On the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), both the visual functioning and socioemotional subscales improved at 4 months by a mean of more than 5 units, and this improvement was maintained. This level of change corresponds to a 15-letter change in BCVA (in wet AMD) and is clinically meaningful, according to Dr Gregori.

This particular RPE preparation will not be moving into phase 3 trials, however, because of changes in regulations by the US Food and Drug Administration (FDA). A new, compliant cell line will be tested in a phase 1b/2 study in patients with severe vision impairment to blindness.

Study From Dr Banin's Group

Dr Banin and his colleagues are conducting an open-label sequential phase 1/2a "concentration-finding and efficacy study" of hESC-derived allogeneic RPE cells using a xenograft-free cell line called HAD-C 102. They are using a special method of direct differentiation to ensure the preparation is "pure" and not tainted by undifferentiated cells, which can precipitate tumors, he said.

Patients with advanced dry AMD and geographic atrophy, with BCVA ≤ 20/200, are enrolling at four sites in Israel and three in the United States. At the conference, he described outcomes in six patients.

"Subretinal transplantation of hESC-derived RPE appears well tolerated," Dr Banin reported. There were no treatment-related systemic serious adverse events and no unexpected ocular adverse events. New or worsening epiretinal membrane formation that did not require surgical removal was seen in five patients.

BCVA remained stable, and subretinal pigmentation that correlates with irregular subretinal hyper-reflectance on optical coherence tomography is evident in five of six patients, suggesting the presence of cells in the subretinal space, he reported.

He presented images that seemed to show subretinal "layering" of transplanted hESC-RPE a few months after the surgery. It is unknown whether these changes represent engraftment and survival of the transplanted cells or a response to the transplantation. "Data from our work in the pig model may support the former," he commented.

Both investigators said the ultimate goal is to treat earlier in the disease, which might prolong the life of the photoreceptors and maintain vision.

Is Another Stem Cell Approach Preferable?

During the press briefing, researchers also discussed another, more individualized approach to RPE transplantation that uses induced pluripotent stem cells (iPS) derived from a patient's own skin biopsy. The qualities of iPS cells are very similar to those of embryonic stem cells, but as they come from the patients themselves, immunosuppression is not necessary.

Stephen R. Russell, MD, from the University of Iowa in Iowa City, is performing research using iPS that target photoreceptors. "We are producing iPS cells from the patient's skin biopsy. There are no immunosuppression issues with this approach, which is a good thing because giving immunosuppression to older patients is difficult…. But for each individual patient a cell line must be established."

Having observed that about 80% of injected cells are ultimately lost after a single injection, Dr Russell and his team developed a medium to harness them: a 3D-printed biodegradable matrix that also goes into the subretinal space.

"We are seeing whether it's financially viable to use iPS in a personalized medicine approach [to treat retinal degeneration]. We think the biggest hurdle, however, will not be cost but regulatory issues," he said. "When you modify the patient's own cells, you must go through the entire FDA approval process, as if it's a novel drug. It's prohibitive for most situations…. It's a much more complicated approach, which is one reason we are struggling to get FDA approval to get started."

Irene Maumenee, MD, from Columbia University Medical Center in New York City and the AAO's 2017 Laureate for her work in ocular genetics, commented on the field. "I think it's a reasonable approach to use stem cells from the patient's own skin-derived tissue. That way, you are eliminating an immune issue, but it's outrageously expensive," she noted.

She also questioned whether any form of RPE cell transplantation could really halt retinal degeneration. You basically treat a small area of the retina, but it's a destructive process that is still going on in other cells," she said. "But in dry AMD we don't have any real treatment, and this would certainly answer a big treatment need."

Dr Banin is a consultant for Cell Cure, which is developing OpRegen, and who sponsored the trial. Dr Gregori consults for Regeneron. Dr Gregori's trial was sponsored by the Astellas Institute for Regenerative Medicine. Dr Maumenee disclosed no relevant financial relationships.

American Academy of Ophthalmology (AAO) 2017 Annual Meeting: Abstracts PA096 and PA097. Presented November 14, 2017.

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