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Retinitis Pigmentosa
 - Cell Therapy Approaches

Retinal pigmented epithelium (RPE) degenerative diseases are a family of diseases in which the many functions of the RPE, an essential part of the retina, are impaired. These diseases include age-related macular degeneration (AMD), Stargardt's macular dystrophy (SMD) and retinitis pigmentosa (RP). In AMD, extracellular matrix is deposited on the RPE, impairing its many functions and inducing retinal dysfunction. In SMD, there is an abnormal deposit of lipofuscin on the RPE, which eventually degrades, leading to photoreceptor loss, and a consequential decrease in central vision. In RP, gene mutations cause the rod cells to degenerate, resulting in a loss of night vision and to eventual death of cone photoreceptors, causing total blindness. All of these diseases have limited conventional treatments and can lead to total blindness. The therapeutic goals in treating retinal diseases include arrest of disease progression and restoration of RPE function. These can be achieved by neuroprotection, replacement of the degenerated cells, generation of artificial, transplantable retinas and gene therapy or long-term delivery of therapeutic agents. The retina is considered by many as an extension of the brain and as such, has poor regenerative capacities. However, it has the advantage of being an accessible tissue, making it a feasible therapeutic target. 

Cell Therapy Approaches

The eye is considered an immune-privileged organ, reducing the chance of rejection of transplanted cells. In addition, its easily accessible location makes it very attractive for transplantation treatments. Many animal studies have been performed to assess cell therapy of ophthalmologic diseases.  Several ongoing clinical trials are testing the safety and efficacy of cell therapies in RPE-related diseases. Cell therapy can be utilized to achieve either neuroprotection or cell replacement and can be administered intravitreally, subretinally and systemically. To obtain neuroprotection, the cells remain undifferentiated induce tissue repair or preserve function by altering the cellular microenvironment, either by releasing cytokines or cell-to-cell interactions. The cell replacement approach utilizes differentiated cells, such as RPE or photoreceptors, that have been isolated, expanded, and derived from pluripotent embryonic, adult stem cells induced pluripotent cells, to replace the damaged native cells and to restore retinal function.  The Royal College of Surgeons (RCS) rats are a commonly studied model that displays inherited retinal degeneration.


Mesenchymal stem cells derived either from the bone marrow, umbilical cord or from the adipose tissue have shown ambiguous results in their ability to differentiate into photoreceptors in vivo. However, there is evidence that they serve a neuroprotective role, delaying retinal degeneration and preserving retinal function in animal models even when administered systemically.

Genetically modified cells are human stem cells genetically engineered to secrete the neurotrophic cytokine CTNF and are delivered by an intraocular encapsulated technology device (NT-501). This cell therapy slowed the progression of vision loss associated with geographic atrophy in humans.
Umbilical tissue-derived cells preserved retinal function following transplantation into RCS rats. The cells remained confined to the subretinal space and did not differentiate into neurons, suggesting that photoreceptor preservation was mediated by the release of trophic factors or cell-to-cell interactions and not by cell replacement. This cell therapy is currently being assessed in clinical trials and had led to improved vision in 50% of the treated AMD patients.
HuCNS-SC® is a highly purified fetal brain-derived human central nervous system stem cell population. The cells have been tested in AMD patients, following demonstration of their neuroprotective abilities in animals, preservation of visual acuity in rats and protection of the retina from progressive degeneration.

Bone marrow-derived mononuclear cells have been intravitreally delivered in advanced degenerative retinopathy patients; no detectable structural or functional toxicity was observed over a period of 10 months. There were slight improvements in visual function, yet further studies will be required. The therapeutic value of these cells in RPE-related diseases has been attributed to the trophic effect of the mononuclear cells on the vascular bed.

Bone marrow-derived hematopoietic stem cells (HSCs, CD34+) are also under evaluation in clinical trials for their potential trophic effects on the RPE. They have been shown to rapidly incorporate into the retinal vasculature and release trophic factors in animal models.

Combined administration of Flt3-ligand (FL) and granulocyte colony-stimulating factor (G-CSF) has a synergistic effect on mobilization of HSCs and facilitating cells (FC, CD8+/TCR−) into the periphery. The cells mobilized to the site of injury and expressed RPE lineage markers in an animal model.

Human very small embryonic-like (VSELTM) stem cells are under investigation for application in cases of macular degeneration. These cells migrate and integrate into damaged areas.


Cell replacement

Induced pluripotent stem cells (iPSCs), generated from a patient’s own cells, can reduce the need for immunoprotective post-transplantation regimens. However, pluripotent stem cells can undergo unwanted overgrowth or form tumors. This concern is particularly acute for iPSCs. iPSCs can be differentiated into functional iPS-RPEs and their transplantation in an animal model facilitated the short-term maintenance of photoreceptors through phagocytosis of the outer segments of photoreceptors (one of the RPE roles). The iPS-RPEs are lost in the long-term, while visual function is maintained, suggesting a secondary protective host cellular response. The primary drawback of use of iPSCs as compared with hESCs, is that therapy of genetic disease using autologous cells requires gene therapy. iPSCs are currently being assessed for treatment of AMD and are soon to be tested in clinical trials.

Human embryonic stem cells (hESCs) can be induced to form RPE-like cells by either spontaneous or directed differentiation. Although yield and speed are greater with the directed methods, the exogenous factors required to drive stem cells down a neural and eye field pathway are expensive, and the associated cell culture techniques are laborious. Furthermore, the factors used are often derived from bacterial and animal sources, which can add complexity to the regulatory process preceding human therapies. hESC-derived RPEs resemble RPEs in morphology, polarity, phagocytosis, tight junctions and retinol cycling. hESC-derived RPEs transplanted into the subretinal space of RCS rats or Elov14 mice (a model for SMD) slowed the photoreceptor degeneration, provided long-term functional rescue and lasted for a long period (>220 days). hESC-derived RPEs did not form teratomas or display any other evidence of dysplasia in immunodeficient mice. In contrast,hESC-derived neural precursor cells that are also considered as therapeutic cells in RPE-degenerative diseases induced the development of tumors in mice.

hESC-derived retinal progenitor cells transplanted into the subretinal space of Crx−/− adult mice restored visual sensitivity to flashes of light. No teratomas were seen within the 4–6 week post-transplantation period.

Clinical trials assessing transplantion of hESC-derived RPEs, MA09-hRPE, into both Stargardt disease and dry AMD patients, found them to be safe and to improve visual acuity during the first 18 months following treatment. There were no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. Several companies have developed hESC-derived RPEs for the treatment of AMD such as, Pf-05206388 OpRegen®, that are at different stages of clinical development.

Tissue transplantation: Fetal retinal sheet transplantation improved visual acuity in patients but is limited by the availability of fetal retina. A three-dimensional neural retina can be grown in culture from mouse ESCs cultured with extracellular matrix components, to yield optic vesicles. The optic vesicles undergo dynamic morphogenesis to form bilayered cups expressing the molecular markers characteristic of both the neural retina and the RPE, which becomes visibly pigmented. The retinal progenitor cells that develop can then be further differentiated into the main retinal neuronal cell types including photoreceptors. hESCs and iPSCs have been grown into optic vesicle-like structures, suggesting they may provide multilayered retinal sheets for transplantation.

Retinitis Pigmentosa