Figure 1. Color fundus photo of a left eye with advanced dry age-related macular degeneration. Geographic atrophy is present in the center of the macula.
Stem cells are specialized cells of the body that possess the ability to self-renew through mitosis and the potency to differentiate into specialized cell types. These cells also possess the ability to regenerate and renew cells that are lost through disease, injury or normal wear and tear.1 Given their potential to re-create lost cellular functions, stem cells have been applied to address specific degenerative diseases of the retina, like geographic atrophy in non-exudative age-related macular degeneration (See Figure 1) and Stargardt’s disease (See Figure 2). There are several clinical programs in different stages of development (See Table 1) and the aim of this review is to describe the current state of these programs as of early 2015.

Embryonic Stem Cells

Human embryonic stem cells (hESC) are the earliest and most basic component of our bodies. They are pluripotent and have the ability to differentiate into all cell types of the body. In theory, hESCs can be made into specific retinal cell types and used to replenish degenerating or malfunctioning cell in many disease states. Animal studies have shown retinal pigment epithelium derived from hESCs can preserve vision after transplantation.2 Ocata Therapeutics Inc. (formerly Advanced Cell Technology) has been running a clinical program since 2011 with a Phase I/II open-label, multicenter, nonrandomized, prospective study to determine the safety and potential efficacy of subretinal RPE cells spontaneously produced from hESCs (MA09-hRPE). In these trials, patients with GA in dry AMD (NCT01344993) and Stargardt’s disease (NCT01345006) had pars plana vitrectomies and were subretinally transplanted with 50,000 to 200,000 hESC-derived RPE cells.

In a recent report, nine eyes in patients with GA and nine eyes in patients with Stargardt’s disease were transplanted and followed for a median of 22 months.3 No treated eyes developed abnormal tissue proliferation, teratoma formation, rejection or inflammation. Of treated eyes, 72 percent had patches of increasing subretinal pigmentation consistent with viable, transplanted RPE. Visual acuity increased in 10 of 18 eyes and decreased in one eye. The remaining seven eyes showed no change in vision at 22 months.

Induced Pluripotent Stem Cells

Induced Pluripotent Stem (iPS) cells are adult cells, such as fibroblasts, that have been genetically reprogrammed to behave like hESCs. Thus, they are fully mature tissue cells that are “regressed” in vitro to become pseudo-hESCs. iPS cells are able to replicate themselves and are pluripotent enough to differentiate into any cell type, just like hESCs. However, it is not known whether they differ in clinically meaningful ways from hESCs.

One potential benefit of iPS cells is that they can be induced from cells harvested from an individual patient. Once prepared, those same cells can be transplanted back into the same person—theoretically reducing the risk of immune rejection.
The Laboratory for Retinal Regeneration at the RIKEN Center in Kobe, Japan has initiated a trial in AMD using iPS-derived RPE cells in sheets. This is the first trial to use iPS cells in AMD and is ongoing. Final results have yet to be reported.4-6

Adult Stem Cells

Like embryonic stem cells, adult stem cells are undifferentiated and can self-renew. However, adult stem cells are not pluripotent and can only differentiate into specific tissue lineages. Theoretically, this reduces the risk of teratoma formation and other hESC-related side effects.

One active eye program that is using adult stem cells is managed by StemCells Inc., which is conducting a Phase I/II study to assess the safety and preliminary efficacy of adult human central nervous system stem cells (HuCNS-SC) in AMD with GA (NCT01632527). HuCNS-SCs were found in pre-clinical models to preserve photoreceptors in the RCS rat model and as adult stem cells, HuCNS-SCs can theoretically only differentiate into cells in the neural lineage.7

In the study, pars plana vitrectomy was performed and HuCNS-SCs were subretinally transplanted. Subjects received either 200,000 or 1 million HuCNS-SCs and were enrolled in two cohorts—one with 20/400 or worse vision and the second with 20/320 to 20/100 vision. The study is now closed to enrollment with 15 subjects from three U.S. clinical sites.

Preliminary data presented to date suggested that the these transplanted cells have not been associated with any adverse reactions. There has been no tumor formation or epiretinal membrane proliferation reported. Eyes that received HuCNS-SCs also had better contrast sensitivity and visual acuity when compared to the fellow control eye. Lastly, treated eyes had about a 70-percent reduction in GA growth rate when compared to the fellow control eye. There is a controlled Phase II study planned to begin this year.

Umbilical Cord Stem Cells

Stem cells from the umbilical cord can contribute to blood and mesenchymal tissue lineages and have the potential to slow degeneration by releasing growth or trophic factors. One such program is being run by Janssen Biotech Inc. The investigational product, CNTO 2476, has been shown to slow vision loss in the RCS rat model after subretinal transplantation.8 A Phase I trial was performed to treat patients with RP (NCT00458575), but this was halted in 2010. The same year, a Phase I/II trial was initiated to assess the safety and preliminary efficacy of these cells in the subretinal space of patients with GA in dry AMD (NCT01226628). In the study, 60,000 to 300,000 cells were subretinally administered in 24 patients using an iTrack Model 275 microcathether.
Figure 2. Color fundus photo of a right eye with Stargardt’s disease. Characteristic pisciform flecks are present in the macula along with a beaten bronze appearance.
Patients were then followed for 12 months. Preliminary results demonstrated improved vision in selected eyes following transplantation, but there were cases of retinal detachments following surgery—perhaps owing to the technical challenges related to delivering cells using a subretinal microcathether.

Bone Marrow Stem Cells

Bone Marrow Stem Cells (BMSC) have been shown to rescue retinal degeneration in mouse models.9,10 Early clinical trials were conducted to evaluate the short-term safety (10 months) of 1 million cells in three patients with retinitis pigmentosa and two patients with cone-rod dystrophy.11,12 No detectable structural or functional toxicity was observed. Current studies included intravitreal injections of 1 million BMSCs in RP patients in Brazil (NCT01560715) and Thailand (NCT01531348), AMD patients in Brazil (NCT01518127) and ischemic retinopathy patients in Brazil (NCT01518842). Results have yet to be reported.

The use of stem cells to treat retinal disease has gone from the theoretical to proof of concept to controlled clinical trials. The next few years will be telling and should provide adequate data to determine whether this treatment approach will be both efficacious and well-tolerated.  REVIEW

Dr. Leng is the director of ophthalmic diagnostics at the Byers Eye Institute at Stanford and is a clinical assistant professor of ophthalmology at the Stanford University School of Medicine. He is an investigator for StemCells Inc. He can be reached via phone: (650) 498 4264; fax: (888) 565 2640; or e-mail:

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