The prospect of stem cell therapy to treat vision loss resulting from various retinal disorders is exciting. Stem cell therapies are currently being explored in phase 1 and 2 clinical trials for retinal degenerative diseases (RDDs) such as age-related macular degeneration (AMD), inherited retinal dystrophies, and retinal vascular disorders. Positive reports in these early clinical trials have offered hope for those with vision loss from retinal disease.

For some patients, the promise of stem cell therapies cannot come quick enough. Unregulated “cell-therapy centers” have emerged, boasting their ability to cure various retinal diseases using fee-for-service “stem cell” treatments that have not been characterized. These unregulated treatments have resulted in severe vision loss in some patients.¹ Despite broad media coverage of these incidents, many of these clinics continue to operate.^2,3 Thus, it is important that eye care providers stay up to date on the current literature on stem cell therapies to help counsel their patients. This article aims to provide an overview on the current state of stem cell therapies for retinal disorders.

STEM CELLS

To most people, “stem cells” mean pluripotent cells, meaning cells that have potential to differentiate into any cell of interest. The 2 types of pluripotent stem cells used in clinical trials are human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Embryonic stem cells are derived from the inner cell mass of a blastocyst, which is a preimplantation embryo about 4 to 5 days after fertilization. For this reason, the use of these allogeneic hESCs raises ethical issues. In contrast, iPSCs are obtained by taking adult somatic cells and genetically reprogramming the cells to behave like ESCs. This approach avoids ethical and rejection issues.

Pluripotent stem cells cannot be administered without differentiating the cells because they can form teratomas. Several earlier clinical trials have explored the use of allogeneic retinal pigment epithelial (RPE) cells differentiated from hESCs to treat retinal degenerative conditions, such as AMD. This was done because the development of iPSCs was relatively new and challenging. However, the use of these allogeneic hESC-derived cells requires immunosuppression to minimize the rejection of the drafted cells. In contrast, autologous iPSCs can be derived from the patient’s own differentiated cell populations, such as blood and skin, and may offer enhanced immune tolerance for future clinical trials compared to cells derived from allogeneic hESCs.

Multipotent stem cells are also being explored in clinical trials for retinal disorders. They include autologous CD34+ stem cells from bone marrow and allogeneic fetal retinal progenitor cells. These multipotent cells are partially differentiated and have a more limited potential to differentiate into various cells. However, they can release trophic factors and enhance tissue repair.

The goal of stem cell therapy is to either replace the damaged tissue or repair the damaged tissue via paracrine effects. Tissue replacement primarily uses pluripotent stem cells such as hESCs or iPSCs. Repair of damaged tissue via paracrine trophic effects is the goal of multipotent stem cell therapy. All clinical trials discussed in this article are trials that are being conducted using cells that have been well characterized and harvested under good manufacturing practice (GMP) conditions for patient safety (Table 1). Clinical trials in the United States are being conducted under an investigational new drug clearance from the Food and Drug Administration (FDA).

TISSUE REPLACEMENT

Tissue replacement is the goal for clinical trials using RPE cells derived from pluripotent stem cells. For conditions like AMD and Stargardt macular dystrophy (SMD), degeneration of the RPE is the natural course. The RPE has been of particular interest because its function does not depend on nerve synapses and its monolayer nature makes it easier to develop.^4,5 The RPE cells can be replaced in these degenerative conditions via subretinal injection of RPE cells or by subretinal transplantation of a RPE monolayer sheet. To prevent immune rejection of the allogeneic hESC-RPE cells, many clinical trials have instituted various oral immunosuppressants. In trials using the autologous iPSC-RPE cells, no immunosuppression has been used.

Two phase 1/2 open-label clinical trials sponsored by Astellas Pharma have been conducted in eyes with vision loss from SMD using subretinal injection of hESC-RPE cell suspensions.^6,7 Both studies showed that this treatment was feasible and relatively well tolerated except for a few eyes that developed epiretinal membrane and some participants who developed side effects from systemic immunosuppression.⁸ Unfortunately, the visual gain noted in the first study was not seen in the second study.^8,9

A phase 1/2a open-label clinical trial sponsored by Regenerative Patch Technologies is evaluating the safety and feasibility of transplanting hESC-RPE cells grown as a monolayer in eyes with geographic atrophy secondary to dry AMD.¹⁰ The RPE monolayer is grown in a scaffold and the implant is surgically placed under the macula in the area of geographic atrophy. After 1 year, the clinical trial reported that the implant was tolerated except for hemorrhage and pigment epithelial detachment likely associated with surgical placement. There was no associated immune or inflammatory response.¹¹ Additionally, this trial showed 2-year survival and function on postmortem histology in 1 patient.¹¹ Although this was an open-label study, early visual outcomes seem promising with about 60% of patients showing stable or improved vision, whereas about 80% of the patients’ untreated eyes had worsening of vision.^11,12

A group in Japan was successful in transplanting an iPSC-RPE monolayer in a patient with vision loss from exudative AMD and it was well tolerated for 1 year.¹³ However, there was no visual gain, and the study was put on hold due to genetic instability of subsequently generated iPSCs. More recently, the National Eye Institute has started enrolling for a phase 1/2 clinical trial exploring the safety and tolerability of subretinal placement of iPSC-RPE monolayer grown in a scaffold. Patients with vision loss from geographic atrophy from AMD are being targeted for this clinical trial.¹⁴

TISSUE REPAIR

Besides tissue replacement, tissue repair has been another focus of stem cell therapy for retinal diseases. Multipotent stem cells release trophic factors, which have been suggested to help repair the retina for various conditions. Because multipotent stem cells do not need to be differentiated, they are easier to prepare in the lab. However, the purity of the cellular product needs to be confirmed before administering to patients. Intravitreal injection is a feasible approach that is being explored since the stem cells do not have to be physically present within the damaged layer of the retina to have its primary regenerative effects.

Examples of multipotent human stem cells that can repair damaged tissue include CD34+ stem cells and mesenchymal stem cells (MSCs). These cells are natural repair cells in our body.¹³ They can be found in adult bone marrow, adipose tissue, and many other organs. Human bone marrow contains both CD34+ stem cells and MSCs, which have both been explored in clinical trials.

Mesenchymal stem cells in bone marrow are much fewer in number than CD34+ cells but can be readily grown in tissue culture.¹⁵ Both autologous and allogeneic MSCs have been administered intravitreally and subretinally in eyes with retinal degeneration. Both routes have been associated with abnormal intraocular cell proliferation, raising safety concerns.^16,17

CD34+ stem cells, in contrast, do not readily expand in culture and may be safer stem cells to explore for clinical application.¹³ These CD34+ stem cells are mobilized into the circulation in response to tissue injury, hone in on damaged tissue and promote repair.¹³ To maximize the repair potential of these cells, our group conducted a phase 1 study exploring intravitreal injection of autologous CD34+ stem cells from bone marrow in eyes with vision loss from retinal disorders.¹⁸ The study found that intravitreal injection of autologous CD34+ stem cells is feasible and well tolerated in eyes with retinal degeneration or ischemia.¹⁹ Because some efficacy signals were noted in the open-label phase 1 study, a phase 1/2 clinical trial is being conducted currently to further explore this autologous stem cell therapy.^20,21 First is a phase 1/2 double-masked, sham-controlled, randomized study sponsored by the National Eye Institute exploring this cell therapy in eyes with vision loss from central retinal vein occlusion (the TRUST study). Second is a phase 1 open-label study exploring this cell therapy in eyes with retinitis pigmentosa.

Another multipotent stem cell being explored in clinical trial is the allogeneic fetal retinal progenitor cell. A phase 1/2a clinical trial sponsored by jCyte evaluating intravitreal injection of these cells in eyes with retinitis pigmentosa has shown relative safety except for mild ocular inflammation.²² Improvement in perimetry was noted suggestive of efficacy.²³ A phase 2b double-masked study is ongoing to evaluate efficacy and safety of repeated intravitreal injection of these cells.²⁴

SO-CALLED STEM CELL THERAPY CENTERS

There has been a large amount of public intrigue regarding the possibilities of stem cell therapy for various diseases. To take advantage of this, numerous unregulated fee-for-service clinics referred to as stem cell centers have popped up throughout the country. Some of these centers are posted on ClinicalTrials.gov to feign legitimacy.²⁵ These centers administer cells that have not been characterized or properly purified. Several cases of severe irreversible vision loss, sometimes in both eyes, have been reported in the literature.¹ There has been some progress on this front, with the FDA winning a lawsuit against a stem cell center in Florida responsible for blinding a patient with AMD.² This ruling may allow the FDA to have the power to stop the operations of future unregulated stem cell therapy clinics.^2,3 Even with this recent ruling, these clinics still continue to operate. As retina specialists, it is imperative we warn our patients to stay away from these centers and to educate them on the current data.

FUTURE DIRECTIONS

The research surrounding iPSC development has evolved such that retinal organoids can be now created from iPSCs.²⁶ These retinal organoids have been shown to mimic cone photoreceptors, exhibiting robust light-evoked responses.²⁶ As such, they have been used as in vitro models to study the retina. Prior studies that focused on photoreceptor replacement were met with the challenge that transplanted cells seemed to only transfer cytoplasmic material to existing photoreceptors rather than fully integrate.²⁷ Recently, it has been shown that retinal organoids have the capability to make functional synapses.²⁸ Though they have not yet been used in clinical trials, it is exciting to consider the potential future use of these retinal organoids for tissue replacement.

Various other new approaches to cell therapy continue to be explored in preclinical studies for retinal regeneration. It is beyond the scope of this article to provide a comprehensive review of these approaches, but some of these novel approaches may lead to new future clinical trials.

SUMMARY

Although stem cell therapy seems promising, it remains an experimental treatment for retinal disorders. As such, stem cell treatments should be administered only as part of regulated and closely monitored clinical trials and using well characterized cells harvested and manufactured under GMP conditions. The full safety and potential efficacy of this novel approach to retinal regeneration is still unknown and continues to be investigated in clinical trials. RP

REFERENCES

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