Stem cells may be the next frontier for retinal disease

Several classes of stem cells could offer potential treatments with differing benefits and risks.

Daniele Veritti

Stem cells are viewed as both an ethical controversy and an effective tool for the treatment of human ophthalmic diseases. Research shows promise for stem cells to become a future option in treating ocular conditions, including proliferative diabetic retinopathy and age-related macular degeneration.

Stem cells are considered a category of self-renewing, multipotential cells that are highly proliferative and can be categorized as human embryonic stem cells (hESCs), adult stem cells (adult SCs), induced pluripotent stem cells (iPSCs) or parthenogenetic stem cells (hpSCs).

hESCs

HESCs are cultures of cells derived from oocytes in the early phases of development. They have unlimited potential for self-renewal and capability to differentiate into every cell type of the human body. However, the optimal signals to control differentiation still need to be better defined. The main problems involving the allogenic transplant of undifferentiated hESCs in a graft are the risk of an immunological response in the receiver and the potential to develop malignant transformations, according to findings by Hentze and colleagues.

Furthermore, hESCs are derived from a human embryo, and this is related to important ethical, political and theological disputes. But because of their ability of unlimited expansion and pluripotency, hESCs may be a good choice for the treatment of human ocular pathologies.

Adult SCs

Adult SCs are derived from adult tissues with a limited ability to differentiate into functional cells. They are older and less powerful than other stem cells. They are rare and generally proliferate poorly, making it difficult to produce therapeutic amounts.

The limited flexibility of adult SCs reduces the risk of teratoma formation. Moreover, the use of adult SCs in medical research is not as controversial as hESCs because the production of adult SCs does not require the use and elimination of human embryos or an extensive genomic manipulation.

iPSCs

IPSCs are adult differentiated cells that are artificially reprogrammed to earlier development stages. The development of such cells does not involve the use of human embryos and avoids immune rejection because they are derived entirely from the patient. However, the production of reprogrammed cells may give rise to an unknown genetic alteration that may have a dramatic biological consequence. Moreover, autologous transplant of iPSCs have significantly limited clinical use in hereditary disease. Finally, the procedures to isolate these stem cells are expensive and time-consuming.

hpSCs

HpSCs are derived from chemical activation of human oocytes, a procedure discovered by International Stem Cell Corporation. These stem cells are as pluripotent and proliferative as hESCs, avoiding the ethical, political and religious controversies regarding the manipulation of human embryos. HpSCs can also be produced in a homozygous form, reducing the risk of immune rejection.

Stem cell research

Stem cell-based therapy has been tested in animal models for several ocular diseases.

In recent studies, the presence of a limited number of stem cells in the retinal ciliary margin has been documented in the adult human eye. The degeneration of retinal neural cells is considered a hallmark of ocular diseases, including AMD, retinitis pigmentosa, proliferative diabetic retinopathy, end-stage glaucoma, proliferative vitreoretinopathy and inherited retinal disease. In these cases, the loss of photoreceptors is the primary cause of blindness. This can result from dysfunction in either the photoreceptor cells or the underlying retinal pigment epithelium that support their survival.

As suggested by recent studies, it may be more appropriate to use adult SCs that are already differentiated to become retinal neurons. At present, anti-angiogenic agents, laser photocoagulation and surgical treatments represent the only methods available to delay the pathology progression, but it is impossible to prevent the long-term consequences of these diseases. Stem cell-based therapies could potentially replace the damaged neurons in the neuronal network that is not yet damaged, according to a study by Limb and colleagues.

Studies on the potential of stem cells to regenerate retinal pigment epithelium cells for transplantation in patients with AMD, proliferative diabetic retinopathy and other retinal conditions are being actively conducted by several biopharmaceutical companies. The use of hESCs to treat Stargardt’s disease may represent the first clinical trial program to implant hESCs into human eyes.

In the case that one of these projects is successful, we may be on the brink of a new, exciting era for ophthalmology with the possibility to prevent blindness for millions of patients.

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• Daniele Veritti, MD, can be reached at Department of Ophthalmology, University of Udine, p.le S. Maria della Misericordia, 33100 Udine, Italy 33100; +39-0432-559907; email: verittidaniele@gmail.com.
• Disclosures: Dr. Veritti and Dr. Sarao have no direct financial interest in the products discussed in this article, nor are they paid consultants for any companies mentioned.