Stem Cell Therapy in Retinal Diseases

Current preclinical research results and upcoming clinical trials

Stem Cell Therapy in Retinal Diseases

Current preclinical research results and upcoming clinical trials.

Tim U. Krohne, MD, FEBO

The recent few months has seen a marked increase in lay media coverage of stem cell therapies for retinal diseases, mainly due to the FDA's announcement allowing a biotech company in the United States to move forward with two clinical trials that test embryonic stem cell–based therapies in Stargardt's disease and atrophic age-related macular degeneration. The high media interest is partly due to the fact that these trials represent two of the first three clinical trials of pluripotent stem cell-based therapies ever, together with a study on spinal-cord injury that started recruiting patients last year.

In parallel to the increased media attention to stem cell therapies for eye diseases, a growing number of commercial stem cell clinics worldwide are advertising largely unproven stem cell therapies for retinal disorders, as well as other medical conditions.1,2 Together, both developments are resulting in a strong increase in patient awareness of stem cell therapies for retinal diseases, and ophthalmologists are being approached more frequently for recommendations regarding this new treatment approach.

This review summarizes the current state of preclinical and clinical research on stem cells to facilitate informed patient counseling regarding current and future clinical applications of stem cells for retinal diseases.


Stem cells are defined by their unique capabilities of unlimited self-renewal and of differentiation into all, or at least several different, cell types of the body (so-called pluri- and multipotency, respectively). Classically, stem cells are divided into adult (or somatic) stem cells and pluripotent (eg, embryonic) stem cells.

Adult stem cells reside in many different tissues of the human body and provide those tissues with the capability of lifelong self-repair and renewal. Examples include limbal stem cells of the corneal epithelium, hematopoietic stem cells of the bone marrow, skin stem cells in the epidermis, and epithelial stem cells of the gastrointestinal tract. These cells are not pluri- but multipotent—ie, their differentiation capacity is restricted to certain cell types.

In contrast, pluripotent stem cells are able to differentiate into all cell types of the human body. The classical pluripotent stem cell is the embryonic stem cell (ESC). Human ESCs are derived from the inner cell mass of the five-day stage embryo, ie, the blastocyst. While earlier methods to generate ESCs were associated with the destruction of the embryo, recently described techniques allow for extraction of only a single ESC without destruction of the embryo,3 similar to the technique used in preimplantation genetic diagnosis.

Only recently, a revolutionary new technique was described that allows for generation of pluripotent stem cells without using embryonic tissue at all. Essentially, it was found that any adult human cell, such as skin fibroblasts, can be treated with a process of genetic modification using the introduction of four defined genetic factors.4,5 This procedure reprograms the cells into so-called induced pluripotent stem cells (iPSCs), which closely resemble ESCs in their pluripotent differentiation potential.


Adult stem cells, such as bone marrow–derived hematopoietic stem cells, can be obtained from the patient him- or herself and thus do not cause rejection when used as autologous grafts. In addition to blood cell–forming stem cells, bone marrow contains other types of stem cells, including those that can form vascular endothelial cells. Such bone marrow–derived cells have been shown in animal models to have positive effects on retinal diseases.6

For example, a subpopulation of bone marrow cells (lineage-negative hematopoietic stem cells) has been demonstrated to incorporate into developing blood vessels following intravitreal injections in neonatal mice, as well as to preserve retinal vasculature and provide neuronal retinal rescue in mice with hereditary retinal disease.7 In addition, some of these cells incorporated into the retina, differentiated into microglia cells, and provided retinal vascular stabilization and repair when injected intravitreally in a mouse model of ischemia-mediated neovascular retinopathy.8 These results demonstrate that intravitreally injected, bone marrow–derived adult stem cells are capable of both incorporating into the retina and providing paracrine effects on the diseased retinal vasculature that could be used therapeutically in human retinal diseases.


In contrast to retinal vascular diseases, most degenerative and hereditary retinopathies require therapeutic rescue, supplementation or replacement of diseased cells in the outer retina, in particular RPE cells and/or photoreceptor cells.6 Pluripotent stem cells, including both ESCs and iPSCs, can be differentiated into such cells under appropriate cell culture conditions, and the resulting cells could then be used as therapeutic cellular grafts.

In particular, RPE cells have been consistently generated from pluripotent stem cells, and the resulting cells resemble terminally differentiated RPE cells in morphology and function.9-11 Different groups have demonstrated that subretinal transplantation of stem cell–derived RPE grafts into animal models of RPE-mediated retinal degeneration results in integration and survival of these cells and associated rescue of retinal degeneration.12-14

RPE-mediated retinal degenerations, such as AMD, may represent an ideal target for such a pluripotent stem cell–based therapy for a number of reasons. Not only are the protocols to generate fully differentiated RPE cells from stem cells already well established, but RPE cells can also be delivered directly into the correct location under the retina, eg, by a subretinal injection of cell suspension or by surgical implantation of a preformed RPE cell monolayer on a suitable carrier matrix.

Moreover, unlike neuronal grafts, transplanted RPE cells would not require synaptic integration into the neuronal retinal network to become functional. Particularly in exudative AMD, surgical extraction of the choroidal neovascular membrane could be accompanied by the subsequent implantation of stem cell–derived RPE cells to cover the surgically induced RPE defect, similar to previous approaches using autologous RPE sheets excised from the peripheral retina.15


The very recently developed iPSCs may, in the future, provide a clinical alternative to ESCs by avoiding many of the problems associated with the therapeutic use of ESCs. iPSCs are not derived from embryonic tissue but from adult cells and can thus be generated without causing ethical problems. The possibility of deriving iPSCs from the patient's own cells, such as from skin biopsy, allows for the generation of autologous grafts that would avoid the need for lifelong immunosuppressive treatment to prevent graft rejection. For hereditary, early-onset retinal diseases, however, the use of autologous cell replacement therapy with iPSCs is limited by the fact that iPSC-derived autologous grafts would still carry the genetic defects, at least unless these defects were genetically corrected prior to cell reimplantation.

Figure 1. Geographic atrophy in AMD (A,B) and Stargardt's disease (C,D) are the targets for the first clinical trials of pluripotent, stem cell–based therapies in ophthalmology. (A,C: fundus color imaging; B,D: fundus autofluorescence cSLO imaging.)

Before any clinical application of iPSC, however, safety concerns have to be resolved, and these concerns result from the potential risk of malignant transformation of iPSC-derived cellular grafts due to the oncogenic properties of the transcription factors required by current reprogramming protocols, as well as the factors' retroviral delivery and random integration. Extensive research efforts are underway to establish new reprogramming strategies that avoid these issues, eg, by replacing transcription factors with small molecules.16 Eventually, iPSCs entirely free of genetic alterations would be required for clinical application.

In addition to the clinical applications of iPSCs as cellular grafts for transplantation, iPSCs also provide exciting new prospects for preclinical research due to their potential of modeling diseases in the cell-culture dish. For this process, a sample of somatic cells is taken from a patient suffering from the disease of interest. These cells are then reprogrammed into iPSCs and subsequently differentiated into the cell type primarily affected by the disease.

Particularly in hereditary, early-onset diseases, this approach can be useful in generating cultures of cells exhibiting the disease phenotype of the donor patient. In the area of ophthalmology, this approach has been recently demonstrated for different forms of retinitis pigmentosa.17 These cell culture disease models can then be used for the screening of new drugs or for basic research on disease pathogenesis to identify novel targets for pharmaceutical intervention.


Two clinical trials for stem cell–based therapies in retinal diseases have now been approved by the FDA, both initiated by Advanced Cell Technology (Santa Monica, CA). According to the company's press releases and web site, Advanced Cell Technology plans to include patients with Stargardt's disease and geographic atrophy secondary to AMD. Patients will receive a subretinal injection of human ESCs that were differentiated into RPE cells prior to injection. The ESC lines to be used will be generated without destruction of the embryo using a single-cell biopsy method.3

The two phase 1/2 trials will include 12 patients each, and recruitment is expected to start this year. It is exciting to see that, once again, ophthalmology is at the forefront of medical research and that retinal diseases are among the first clinical indications for which the new technology of stem cell–based therapy will be applied.


Despite a huge body of scientific evidence for the beneficial effects of stem cells in animal models of retinal disorders, stem cell–based therapy for retinal diseases is still an experimental therapy that has not yet been established in clinical trials. Thus, patients should be advised that clinical evidence to support the therapeutic effect of currently available commercial stem cell treatments in retinal diseases is lacking. However, clinical trials, in particular for the use of pluripotent stem cell–based therapies, are underway, and stem cell technology holds great promise for the future therapy of currently untreatable retinal diseases. RP


1. Qiu J. Trading on hope. Nat Biotechnol. 2009;27:790-792.
2. Zarzeczny A, Rachul C, Nisbet M, Caulfield T. Stem cell clinics in the news. Nat Biotechnol. 2010;28:1243-1246.
3. Chung Y, Klimanskaya I, Becker S, et al. Human embryonic stem cell lines generated without embryo destruction. Cell Stem Cell. 2008;2:113-117.
4. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861-872.
5. Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917-1920.
6. Marchetti V, Krohne TU, Friedlander DF, Friedlander M. Stemming vision loss with stem cells. J Clin Invest. 2010;120:3012-3021.
7. Otani A, Dorrell MI, Kinder K, et al. Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells. J Clin Invest. 2004;114:765-774.
8. Ritter MR, Banin E, Moreno SK, Aguilar E, Dorrell MI, Friedlander M. Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. Clin Invest. 2006;116:3266-3276.
9. Buchholz DE, Hikita ST, Rowland TJ, et al. Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells. 2009;27:2427-2434.
10. Lehmann M, Krohne TU, Friedlander DF, et al. Generation of retinal pigment epithelial cells from human induced pluripotent stem cells. Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; Fort Lauderdale, FL; April 11, 2010.
11. Osakada F, Ikeda H, Sasai Y, Takahashi M. Stepwise differentiation of pluripotent stem cells into retinal cells. Nat Protoc. 2009;4:811-824.
12. Carr AJ, Vugler AA, Hikita ST, et al. Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS One. 2009;4:e8152.
13. Idelson M, Alper R, Obolensky A, et al. Directed differentiation of human embryonic stem cells into functional retinal pigment epithelium cells. Cell Stem Cell. 2009;5:396-408.
14. Westenskow PD, Krohne TU, et al. hiPS-RPE derived with OCT4 and small molecules resemble fetal hRPE and prevent photoreceptor degeneration in RCS rats. Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; Fort Lauderdale, FL; April 2011.
15. van Meurs JC, Van Den Biesen PR. 2003. Autologous retinal pigment epithelium and choroid translocation in patients with exudative age-related macular degeneration: short-term follow-up. Am J Ophthalmol. 2003;136:688-695.
16. Zhu S, Li W, Zhou H, et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell. 2010;7:651-555.
17. Jin ZB, Okamoto S, Osakada F, et al. Modeling retinal degeneration using patient-specific induced pluripotent stem cells. PLoS One. 2011;6:e17084.

Tim U. Krohne, MD, FEBO, is on the faculty of the department of ophthalmology at the University of Bonn in Germany. He reports no financial interest in any products mentioned in this article. Dr. Krohne can be reached at