Our Readers Want to Know: What Is the Progress of Stem Cell Research for Eye Disease? Answer: It Has a Very Long Way to Go

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Of all the eye research developments reported on the VisionAware blog, it is stem cell research for eye disease that generates the most inquiries from readers. Many readers request information about how to join a stem cell clinical trial, or find a doctor who will perform stem cell treatments.

In response to these inquiries, my message is always the same: “Although stem cell research has produced interesting results, it is in its very earliest stages and must be subjected to additional, longer-term, rigorous study and clinical trials, encompassing many more years of research. Success in this area is not a foregone conclusion. At present, stem cell research is fraught with numerous stops and starts, high expectations, and frequent disappointments.”

A Small Clinical Trial

The stem cell research that VisionAware has followed most closely involved an 18-patient early-stage clinical trial of human embryonic stem cells (hESC) for the treatment of dry age-related macular degeneration and Stargardt disease.

The research was sponsored by Ocata Therapeutics (formerly Advanced Cell Technology, Inc.) and interim results from these initial surgeries performed in 2011 and 2012 were published in the October 15, 2014 issue of The Lancet, in an article titled Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies.

You can read more about the results of this 18-patient clinical trial at Updated Stem Cell Clinical Trial Results for Stargardt Disease and Dry Macular Degeneration on the VisionAware blog.

Yes, the authors did report encouraging results and gains in vision, but they also emphasized that the purpose of these small early clinical trials was to assess the safety of this new stem cell intervention, stating that “[the cells’] plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumor formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types.”

Please note: In February 2016, Ocata Therapeutics was acquired by Astellas Pharma, Inc., a Tokyo, Japan-based pharmaceutical company.

What Is the Status of Stem Cell Research in 2016? An Answer and Update from Investigative Ophthalmology & Visual Science

This stem cell update, focusing on the 18-patient clinical trial, is titled Subretinal Transplantation of Embryonic Stem Cell–Derived Retinal Pigment Epithelium for the Treatment of Macular Degeneration: An Assessment at 4 Years and is available as an open-source article in Investigative Ophthalmology & Visual Science, the official journal of the Association for Research in Vision and Ophthalmology (ARVO). ARVO is an international organization that encourages and assists research, training, publication, and dissemination of knowledge in vision and ophthalmology, including low vision.

The authors are Steven D. Schwartz; Gavin Tan; Hamid Hosseini; and Aaron Nagiel, from the Stein Eye Institute, University of California Los Angeles Geffen School of Medicine; and the Singapore Eye Research Institute, Singapore National Eye Center. Dr. Schwartz led the surgical team in 2011 that performed the stem cell treatment of the first two patients in the clinical trial.

First, Some Basic Stem Cell Terminology

Here is a brief explanation of some key terms that are used in many types of stem cell research:

  • Pluripotent: A stem cell that has the power to develop into any type of bodily cell or tissue (“pluri” = many; “potent” = having power)
  • Induced pluripotent stem cells (iPSCs): A type of pluripotent stem cell that can be generated or “reprogrammed” directly from adult cells. Induced pluripotent stem cells require viruses to reprogram the cells, which has the potential to cause cancerous tumors.
  • Embryonic stem cells (ESCs): Can form any cell type in the body. However, they are in limited supply, and – due to their origins – have ethical issues attached to their use.
  • Human pluripotent stem cells (hPSCs): The term includes both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs)
  • Autologous: Involving one individual as both donor and recipient
  • Retinal pigment epithelium (RPE) cells: The deepest cells of the retina. The RPE helps to maintain the health of the retinal photoreceptor cells, called rods and cones. These photoreceptor cells are triggered by light to set off a series of electrical and chemical reactions that helps brain to interpret what the eye sees. The degeneration of the RPE cells also leads to the death of the rods and cones and, ultimately, vision.
  • Immunogenic: Causing, or capable of producing, an immune response.

About the Stem Cell Update and Continuing Research

Edited and excerpted from Subretinal Transplantation of Embryonic Stem Cell–Derived Retinal Pigment Epithelium for the Treatment of Macular Degeneration: An Assessment at 4 Years, with the entire report available online:

Safety Issues

Despite the many theoretical advantages of human embryonic stem cells (hESCs) …, there are also [many] safety concerns if the hESC derivatives are to be implanted into humans. The differentiated cell population must be free of pathogens [i.e., bacteria or viruses], possess the characteristics of the differentiated cell, and be free of undifferentiated cells.

… In addition, the cells need to be tested in various pre-clinical models, including immunodeficient animals [i.e., animals with an inability to fight infection], to demonstrate the absence of teratoma formation [i.e., a tumor containing several different types of tissue]; hyperproliferation [i.e., an abnormally high rate of cell reproduction]; or the migration of cells into other [bodily] organs.

Importantly, all studies using the hESC-RPE cells in pre-clinical models showed no evidence of teratoma formation, hyperproliferation, or ectopic tissue formation [i.e., tissue that has migrated into other parts of the body].

Another major consideration in these studies is the possibility that the transplanted cells could initiate an inflammatory response or trigger immunologic rejection. Although cellular rejection itself would be a disappointing outcome, of greater concern is the possibility that an inflammatory reaction in the sub-retinal space could incite further damage to areas of retina that remain functional. Despite cross-species transplantation, preclinical models demonstrated little or no inflammation.

You can read about additional safety, tolerability, and visual improvement outcomes at Study Endpoints: Safety and Tolerability.

Summary and Future Challenges

Pluripotent stem cells have the capacity for unlimited self-renewal and have been proposed as a potential source of therapeutic cells for regenerative medicine. These studies provided the first description of the short- and long-term safety of [hESCs] transplanted into human patients. Given the excellent safety profiles observed thus far, this work sets the foundation for future trials using cellular therapies for regenerative medicine in humans.

Within the confines of these phase 1 trials, the transplanted hESC-RPE cells appear to be well tolerated. None of the 18 patients had an adverse intraocular or systemic event related to the cells. However, a number of patients had adverse events related to the surgery or the immunosuppressive regimen [i.e., drug regimens that suppress the immune, or rejection, response]. So while endpoints such as visual acuity improvements and structural changes seem encouraging, enthusiasm must be tempered.

Initial safety studies such as this one are typically limited by the lack of a masked control group, the advanced disease present at baseline, and the small number of patients. Visual acuity measurements can be unreliable in patients with advanced geographic atrophy.

A second major challenge is the use of solid organ transplant-dose immunosuppressive regimens. Subsequent studies will attempt to reduce the amount of immunosuppression and test whether it is even necessary to any degree.

As always, the burden of proof rests on upcoming randomized, multicenter trials. With more sophisticated multimodal imaging and functional testing such as adaptive optics-based scanning laser ophthalmoscopy and microperimetry, it may be finally possible to determine whether the transplanted cells are having a direct effect on visual function at particular sites in the retina.

Thus, this small 18-patient phase 1 clinical trial represents the beginning of a many-years-long series of trials and refinements. There are many questions that must be answered if the research is able to proceed to larger-scale clinical trials. To repeat: Success in this area is not a foregone conclusion.

About Clinical Trials

Most clinical trials are designated as Phase 1, 2, or 3, based on the questions the study is seeking to answer:

  • In Phase 1 clinical trials, researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe and effective dosage range, and identify possible side effects.
  • In Phase 2 clinical trials, the study drug or treatment is given to a larger group of people to determine if it is effective and to further evaluate its safety.
  • In Phase 3 studies, the study drug or treatment is given to even larger groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
  • In Phase 4 studies, after the United States Food and Drug Administration (FDA) has approved the drug, continuing studies will determine additional information, such as the drug’s risks, side effects, benefits, and optimal use.

VisionAware will provide updates on this stem cell research if and when they become available.

Additional Information