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



≥ 10-Letter


Advanced AMD (N = 9)

Advanced Stargardt Disease (N = 9)


Month 24

Month 12


Treated Eye































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.

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