Stem cell therapies for retinal diseases: Recent trials

Bio Thomas Su, BS is a medical student at Johns Hopkins School of Medicine. Michael Pan, BS is a medical student at the University of Rochester School of Medicine. Juliette E. McGregor, PhD, is an assistant professor of ophthalmology at the Flaum Eye Institute at the University of Rochester. Email: [email protected]  Amir H. Kashani, MD, PhD, is a professor of ophthalmology at Wilmer Eye Institute at Johns Hopkins University. Email: [email protected] Dr. Kashani's disclosures: Carl Zeiss Meditec (research grant, consulting), RegenxBio (consultant), Alcon (consultant), Genentech (consultant), Astellas (consultant), Iceberg Medical (consultant). The other authors have no financial interests to disclose.

Retinal degenerative diseases such as dry age-related macular degeneration, retinitis pigmentosa and Stargardt macular dystrophy are characterized by retinal pigment epithelium atrophy and photoreceptor loss.¹ Current strategies for the treatment of these conditions focus on preserving existing vision and slowing disease progression. While conservative strategies such as nutritional supplementation and optimization of lifestyle factors remain the cornerstone of management in many cases, there are a number of emerging pharmacologic therapies such as complement inhibitors for AMD which have shown promising results.^2-6 However, there are no effective treatments that can restore vision in patients with advanced disease who have already lost retinal tissue that supports vision.

Stem cell therapy is one promising option being explored for the treatment of such late-stage disease, with the intent of either protecting residual tissues via the release of trophic factors or replacing damaged cells.^7,8 In this review, we’ll discuss the development of various stem cell therapies for retinal degenerative diseases (Figure 1) with a focus on clinical trials.

Background on cell therapy

Stem cells have the ability to self-renew indefinitely and to differentiate into multiple lineages. There are several potential sources of stem cells, including embryonic, fetal, and adult somatic cells.⁶ Human embryonic stem cells (hESCs) and fetal stem cells can be harvested from blastocysts and fetal tissue, respectively, but there are legal and ethical issues surrounding this process as well as a practical supply-demand problem.^9,10 Stem cells have also been identified in other reservoirs in adults, such as the bone marrow (BM) or the umbilical cord (UC). These cell populations are more heterogeneous, but cells with specific identities can be isolated and expanded in culture.¹¹ Another possibility surfaced with discovery in the early 2000s that the introduction of a specific set of transcription factors could restore differentiation potential to terminal adult somatic cells. These induced pluripotent stem cells (iPSCs), typically generated from skin fibroblasts or blood cells, have become a less invasive and more accessible means of creating specific cell products for research and therapy.¹² Lastly, there’s a subpopulation of RPE cells which are capable of self-renewal, termed RPE stem cells; these RPESCs can be directly expanded to generate RPE progeny without first undergoing induced de- and re-differentiation. This approach theoretically bypasses limitations of induction, including low efficiency rate and tumorigenic potential.^13,14

Figure 1. Summary of common sources, products and delivery methods used for stem cell therapies. Cell products include suspensions of specific expanded cell populations, discrete monolayers of retinal tissue (RPE and/or PRs) to mimic native anatomy and whole slabs of retinal organoid consisting of PRs with connected interneurons. (Created with assistance from ChatGPT-5.5.) Click image to enlarge.

RPE transplantation

By way of a quick review, the RPE serves to maintain the blood-retinal barrier and support photoreceptor function by phagocytosing used outer segments and recycling photopigment.¹⁵ The RPE has been a primary focus of cell replacement strategies due to its laminar structure and importance in defining the retinal architecture and metabolism.⁶ There are two main methods by which therapeutic RPE cells may be introduced to the subretinal space: injection of a cell suspension or transplantation of a cellular monolayer (with or without an artificial scaffold). The former approach is less invasive and requires a smaller retinotomy, but several clinical trials have shown that RPE cell suspensions don’t spontaneously form a normal monolayer in the subretinal space, and there’s a greater risk of reflux into the vitreous cavity. In addition, RPE cells require adhesion to a substrate to fully polarize and differentiate. Therefore, the functional status of RPE cells in suspension is unclear. Implantation of an RPE monolayer requires a more involved surgical procedure but the results more closely mimic the anatomy and physiology of the tissue to be replaced.^4–6 This approach has been used in several clinical trials as well. Next, we review the results of the most recent such studies focusing on studies that have been published over the past six years. We refer the reader to our previous reviews for more comprehensive discussion of earlier landmark studies.^4–6

• RPE cell suspensions. In 2012 a Phase I/IIa study of subretinal injection of allogeneic hESC-RPE suspensions for treatment of advanced dry AMD and Stargardts was published.¹⁶ The four-year follow-up results for 18 patients demonstrated safety and possible efficacy in half of them.¹⁷ Since that time, several studies using hESC-RPE suspensions have reported similar results.

In 2020, a paper reported one-year results of subretinal injection of HLA-matched allogeneic iPSC-RPE cell suspension without systemic immunosuppressive medications in five patients with exudative AMD.¹⁸ There were two instances of suspected mild rejection which resolved with local administration of steroids, and all five patients developed epiretinal membranes thought to be caused by the reflux of graft cells into the vitreous space. However, the RPE graft survived in all cases, demonstrating the short-term feasibility of conservative management of a potential post-engraftment immune responses. There was neither a notable increase nor decrease in vision one year after the procedure.

In 2021, a paper reported a three-year assessment of a Phase I trial involving subretinal injection of hESC-RPE cells in three patients with SMD.¹⁹ No unexpected serious adverse events were noted during this period, and there was no evidence of abnormal proliferation or immune rejection. The rates of progression in the area of decreased autofluorescence remained within expectations of the natural course of SMD, and best corrected visual acuity improved in one patient and remained stable in the other two. Similarly, researchers reported five-year results from seven patients with SMD who underwent subretinal injection of hESC-RPE cells with no unexpected local or systemic adverse reactions.²⁰ On average, the seven treated eyes had similar visual function and retinal sensitivity compared to the fellow eyes at five years.

A 2023 report performed a 12-month follow-up of 12 patients with advanced SMD who received hESC-RPE cells in suspension via subretinal injection.²¹ No unexpected surgery-related or transplantation-related adverse events occurred over this period, and interestingly, all patients had better final BCVA in operated eyes as compared to baseline.

These promising results have been tempered by several observations. First, the subretinal blebs in these cases often don’t cover the area of RPE atrophy. Second, signs of RPE reconstitution have been limited to very small regions (compared to overall bleb size) where hyper-reflective bands on OCT seem to suggest engrafted RPE. Therefore, while these studies show at least some vision improvement, the mechanisms by which subretinal injection of RPE cell suspensions work aren’t clear and is unlikely to represent direct RPE-photoreceptor mediated vision restoration.

• RPE sheets. In 2017, investigators reported the first use of an autologous iPSC-RPE monolayer after surgical removal of choroidal neovascular membrane for treatment of neovascular AMD²² and subsequent four years of follow-up²³ without unexpected serious adverse events. They found that the sheet had survived in place with slight expansion of the pigmented boundaries and there was no evidence of graft rejection. Further, the thickness of the photoreceptor layer and the choroidal volume were subjectively better at the transplant site compared to non-covered areas. Visual acuity remained stable at around 20/200 over the entire duration of follow-up. Since that time, several studies using monolayers of RPE in various formations have been reported.

In 2018, one of this article’s authors (AHK) and co-workers reported preliminary results on five patients from a Phase I/IIa trial of an allogeneic, HLA-mismatched hESC-RPE sheet on a synthetic scaffold with subsequent follow up on 16 patients at one and three years.^24,25 None of the subjects had unexpected serious adverse events.²⁴ At three years, implanted eyes were more likely than non-implanted eyes to gain >5 Early Treatment Diabetic Retinopathy Study letters of BCVA and were less likely than non-implanted eyes to lose >5 letters, although this signal wasn’t statistically significant. There was no significant difference in fixation ability of either the implanted or the non-implanted eyes at this time point, but one patient demonstrated improvement in retinal sensitivity within and surrounding the area of the implant. One subject in the study passed away two years after implantation from natural causes. Histopathologic analysis of the implanted eye demonstrated survival of the graft in the subretinal space, no evidence of immune response directed at the implant, and expression of rhodopsin in the area of neurosensory retina overlying the implant.²⁶ There were no unanticipated severe implant-related adverse events throughout the study.²⁵

In 2024, an analysis reported a five-year follow-up of scaffold-based hESC-RPE transplantation in two patients with advanced neovascular AMD and acute subretinal hemorrhage.²⁷ Both subjects had some extension of pigmentation beyond the original graft area and no evidence of uncontrolled RPE proliferation or immune rejection. Both subjects also had initial improvements in BCVA, fixation and retinal sensitivity, but these improvements were only sustained in one subject.

These studies suggest that surgical implantation of RPE monolayers more closely mimic the natural RPE appearance in vivo. In all these studies, the pigmentation of the implanted RPE was maintained and the OCT appearance of the implanted cells was consistent with that of RPE. One limitation of these studies is that the patient population had very advanced disease that likely put a ceiling on the potential for visual improvement. Nevertheless, both these studies and those using cell suspensions suggest that RPE transplantation is safe and feasible thereby opening the path for additional studies.

There are at least two promising ongoing studies using RPE monolayer approaches. The first is a Phase I/IIa study of induced pluripotent stem cell derived RPE on a biodegradable scaffold for geographic atrophy that’s ongoing at the National Eye Institute. Another is a Phase IIb study using human embryonic stem cell derived RPE for GA that’s sponsored by Regenerative Patch Technologies.

• Other RPE replacement strategies. An alternative, intermediate approach between suspensions and sheets involves RPE cells grown in monolayers within narrow grooves. These “RPE strips” were successfully injected into the subretinal space of three patients (one with advanced dry AMD and two with RP) using a 31G cannula. A paper described safety and efficacy outcomes of this Phase I/II trial in 2025.²⁸ No unexpected serious adverse events were noted, but a suspected immune reaction and epiretinal membrane formation were observed in one patient each. At the one-year mark, there was a reduction in the abnormal area in all three patients, with one patient also reporting significant vision-related quality of life improvement.

Another option being explored in RPE transplantation is the direct use of adult RPE stem cells isolated from post-mortem tissue and expanded in culture. A 2025 paper reported interim results from the first-in-human study of RPESC-RPE cells delivered as a suspension via subretinal injection in six patients with dry AMD.²⁹ The treatment was well-tolerated with no cell-product-related severe adverse events. Treated eyes had improvements in BCVA, whereas untreated eyes had reduced visual acuity compared to baseline consistent with the natural history of GA. These results suggest that there may be advantages to using this cell type although this method would have all the limitations of cell suspension methods listed above.

Figure 2. Adaptive optics scanning light ophthalmoscope image of a honeycomb scaffold seeded with photoreceptor precursors (red) in the subretinal space of a non-human primate model in vivo. Infrared reflectance image of the scaffold microstructure is overlaid with the false-colored fluorescence image of photoreceptor precursors expressing tdTomato.

Photoreceptor transplantation

The results of RPE transplantation studies described above raise the obvious question of whether a similar approach is viable for photoreceptors as well. Photoreceptor transplantation faces many of the same challenges as RPE transplantation, such as stringent organization and polarity demands. Photoreceptors come in varied types, and they must also functionally integrate with host tissue for proper transduction of visual signals.³⁰ Photoreceptor replacement is still being optimized at the pre-clinical stage. One line of investigation in photoreceptor transplantation is based on human pluripotent stem cell-derived photoreceptor precursors (hPSC-PRPs). These cells are produced within three-dimensional retinal organoids that recapitulate human retinogenesis. Within this category, two main products have shown promise: iPSC-derived retinal sheets^31,32 and suspensions of photoreceptor precursors.^33,34 

In similar fashion to RPE suspensions, direct subretinal injections of purified photoreceptor precursor cells have been associated with inconsistent delivery and reflux into the vitreous cavity, but without the prevalence of epiretinal membrane formation. Better anatomic success has been seen with the use of structured retinal sheets, but synaptic connection has remained limited due to the presence of interneurons and the formation of rosettes. Efforts are underway to use genome editing to optimize donor-host connectivity by depleting the interneurons.³⁵ 

Another method being explored by one of this article’s authors (JEM) is the use of synthetic scaffolds seeded with isolated PRPs.³⁶ To track the survival, distribution, and morphology of transplanted photoreceptors in animal models in vivo, hPSC-PRPs can be genetically engineered to express fluorescent reporter proteins. Pairing this approach with adaptive optics scanning laser ophthalmoscopy, it’s possible to assess both the microstructure of the scaffold and the survival and maturation of the photoreceptor transplant at a cellular level in the living eye (Figure 2).

Photoreceptor cell replacement therapies are now being evaluated in a small number of clinical trials. In 2023, two-year results from the first in-human study of retinal organoid transplantation were published.³⁷ Two subjects with RP were implanted with allogeneic iPSC-derived retinal organoids, which survived with neither immune rejection nor unexpected overgrowth. Visual acuity and visual field both remained stable, but retinal sensitivity decreased across the entire measurement area, including at the points overlying the local transplant site.

Adaptive optics optical computed tomography was performed on one patient who received retinal organoid transplantation.³⁸ It was observed that the implanted region had outer plexiform layer-like lines and reflective particles consistent in appearance with outer segment discs, suggesting that the graft may have developed functional morphology. Another clinical trial which is now underway is the Phase I/IIa CLARICO trial for OpCT-001, the first iPSC-derived cell therapy for primary photoreceptor diseases.

Because of the inherent interdependence of RPE and photoreceptor cells and their concomitant loss in advanced disease, researchers are also investigating co-transplantation of both cell types.³⁹ In a proof-of-concept study involving an immunodeficient laser induced rat model of advanced retinal degeneration researchers demonstrated safe transplantation of a co-graft consisting of a retinal organoid plus a polarized RPE monolayer on a parylene scaffold.⁴⁰ Immunohistochemistry revealed that these co-grafts generated photoreceptors and developed neuronal processes which migrated into the host retina. Visual function assessments using optokinetic nystagmus showed improvement in the implanted animals compared to controls. Further optimization of the co-grafting process is still required, but these results support the translational potential of this technique.

Conclusions and future directions

These recent clinical trials contribute to a growing body of evidence pointing to the safety and feasibility of stem cell therapies when performed with appropriate oversight, expertise and expectation. Overall, well-performed cell-based interventions have been associated with reasonable serious adverse event rates for clinical implementation. Continued research into alternative immunosuppression regimens and modes of delivery may further help reduce risks. Functional improvement has been difficult to demonstrate, partially owing to an inherent limitation of early phase studies in a relatively small sample size and often advanced disease. Efficacy analysis is further complicated by significant heterogeneity in control groups and outcome measures. 

However, improvements in visual acuity, visual field and retinal sensitivity have been noted in preliminary studies, especially those implementing careful patient selection. Further, a recent meta-analysis found that, across a total of 18 studies describing quantitative data from 224 eyes, cell therapy was associated with significantly improved BCVA in AMD, RP and SMD.⁴¹ 

Ultimately, randomized controlled trials with longer follow-up will be critical to establish definitive therapeutic benefit, assess treatment durability and monitor for late-onset or rare adverse effects. It’s clear that, with continued optimization of tissue engineering and graft delivery, stem cells hold tremendous therapeutic potential in retinal degenerative diseases. It’s important to note that poorly done studies (often prematurely claiming effectiveness) have had catastrophic results and we encourage readers to review an NEJM article summarizing these events.⁴² Physicians and patients should exercise caution when considering enrolling in clinical trials that seem to promise or exaggerate positive results, especially if payment for participation is required.⁴² RS

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