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The following is based on an article that originally ran in the May/June 2012 Retina Today, a sister publication of Advanced Ocular Care. The author has updated the contents and tables. More information about companies involved in stem cell research and ongoing clinical trials involving stem cells for ocular applications can be found by following the QR codes embedded in this article.
From an inauspicious start several years ago, the use of stem cells in the treatment of several ocular and retinal diseases has picked up steam over the past year. There are now nearly 30 companies and institutions involved in research and clinical trials using a variety of stem cells for the treatment of more than a dozen degenerative problems found in the eye (Table; Additional Resources), including 14 now in human clinical trials.
WHAT ARE STEM CELLS?
Every organ and tissue in the human body is made up of specialized cells that originated from a pool of stem cells in the very early embryo (embryonic stem cells). Throughout our lives, we rely, to a much more limited degree, on rare deposits of stem cells in certain areas of the body (adult stem cells) to regenerate organs and tissues that are injured or lost, such as skin, hair, blood, and the lining of the gut.
Stem cells are like a blank microchip that can be programmed to perform particular tasks. Stem cells’ pluripotency allows them to develop or differentiate under proper conditions into specialized cells that carry out a specific function, such as in the skin, muscle, liver, or in the eye. Additionally, stem cells can grow extensively without differentiating and give rise to more stem cells—this is referred to as self-renewal. These two characteristics distinguish stem cells from other cells in the body and give stem cells their tremendous therapeutic promise for a wide range of degenerative diseases.
The four most commonly used and described classes of stem cells are embryonic stem cells (embryonic ESCs, or human embryonic stem cells hESCs), induced pluripotent stem cells (ipSCs), adult stem cells (adult SCs), and parthenogenetic stem cells (hpSCs). All four types are used in medical research, although the popularity of research involving ipSCs and hpSCs has grown in recent years.
ESCs are derived from fertilized human eggs (oocytes) in the very early stages of development. They are truly pluripotent, in principle enabling them to become any body tissue, and thus provide tremendous clinical potential. They are, however, associated with significant ethical, political, and religious controversy, because a fertilized egg, under the right circumstances, has the potential to develop into a human being. Of note, one company, Advanced Cell Technology, has devised a method to produce human embryonic stem cells from a blastomere, removing only a few cells without damaging or destroying the embryo.
Another major (albeit much less publicized) issue with ESCs is that, because they are transplanted from one person (the fertilized egg) to another person (the recipient patient) (ie, an allogeneic treatment), therapeutic cells and tissues derived from ESCs may provoke an immune response from the recipient and be rejected.
In contrast, ipSCs are adult and fully differentiated cells (eg, skin cells) that are chemically, physically, genetically, or otherwise driven back to earlier developmental stages. Although creation of such cells does not involve the use or destruction of a fertilized egg, it does require dramatic changes in gene expression that may have an unknown biological impact. As a result, their use will likely be subject to substantial scrutiny by regulatory authorities before approval for therapeutic use. Also, due to immune rejection, ipSCs have to be derived from the patients themselves (ie, autologous therapy), which significantly limits clinical use and adds time and cost that will be increasingly difficult to implement in cost-contained health care systems worldwide. Finally, ipSCs cannot be used for hereditary disease therapy because they bear the same genetic defects as the donor patient.
Adult SCs are rare cells found in various organs or tissues and have a limited ability to differentiate into cells with specific functions. They are older and less powerful than other types. Although these stem cells do not require the use or destruction of a fertilized egg or extensive manipulation of gene expression, they are rare and hard to identify, and they generally proliferate poorly, thus making it hard to produce therapeutic amounts.
Another type of stem cell, hpSCs, are derived from activated human oocytes. Parthenogenesis is a form of asexual reproduction in some amphibians and plants but does not occur naturally in mammals, including humans. Scientists have discovered a process for the chemical activation of human eggs, similar to what the sperm does in normal fertilization, but without sperm. Some companies claim that this process results in hpSCs which are as pluripotent and proliferate as ESCs, yet avoid the ethical, political, and religious controversy around the use or destruction of human embryos with potential for viable human life. Furthermore, because there is no forced change of gene expression patterns, hpSCs are not likely to face the same safety and regulatory hurdle as ipSCs. Most importantly and unique relative to all other stem cell classes, hpSCs can be produced in a simplified immunogenetic (homozygous) form that enables each line to be an immune match for many millions of people.
APPLICATIONS FOR STEM CELLS IN OPHTHALMOLOGY
The Front of the Eye
Scarred and degenerative corneas represent one prime area of research for the use of stem cells. Because of a shortage of donated human corneas for transplantation, especially in populous nations such as India and China (and in developing nations), the use of stem cells to regenerate corneal tissues could become valuable in areas of the world where blindness due to damaged corneas is prevalent.
The Middle of the Eye
There are only a few research programs using stem cells for the middle areas of the eye, specifically in treating glaucoma. NeoStem, Inc., has said that it is working with Schepens Research Institute in using the company’s very small embryonic-like stem cells in the treatment of glaucoma (and age-related macular degeneration [AMD]). Stemedica Cell Technologies claims to be working with the Fyodorov Eye Institute in Moscow on a glaucoma program.
The Back of the Eye
Most of the research efforts involving stem cells appears to be focused on the back of the eye, specifically on retinal tissue and diseases. I have identified areas of interest including regeneration of retinal pigment epithelial cells for the treatment of both dry and wet forms of AMD; replacement of damaged photoreceptors; the growth of artificial retinas for treating AMD; and direct treatments for diseases such as retinitis pigmentosa, retinopathy of prematurity, diabetic retinopathy, Stargardt disease (also known as Stargardt macular dystrophy), retinal vein occlusions, and optic nerve atrophy.
CLINICAL TRIAL STATUS
At the time of this publication, there were 30 institutions and companies actively engaged in research involving stem cells in the United States, South America, Europe, Iran, South Korea, Taiwan, Japan, and China to treat a variety of primarily retinal conditions. It should be noted that Advanced Cell Technology’s clinical trials for both Stargardt disease and dry AMD, at several eye institutes in the United States and Europe, have shown positive results in human patients as reported in The Lancet.1 More than 200 patients worldwide have received stem cell/cell therapy treatments to date.
In its phase 1/2 clinical trials for Stargardt disease and dry AMD, Advanced Cell Technology has recently reported no safety problems and the observation of evidence of engraftment of the transplanted ESC-derived retinal pigment epithelial cells and visual acuity gain in patients treated during the 18 months since the trials were first initiated.2
As stated by Stephen Rose, PhD, chief research officer at The Foundation Fighting Blindness, in his Eye on the Cure blog,3 “Of course, it would be nice if all the parts of our bodies, including our retinas, came with extended warranties so you could just swap them out when they go bad. But now that I think about it, that’s what stem cells might do for us someday.”
Irv Arons is a retired consultant to the ophthalmic industry, and he writes a blog, Irv Arons’ Journal, focused on new technologies, including stem cells and gene therapy, for treating retinal diseases. His blog can be found at http://tinyurl.com/ijablog. Mr. Arons may be reached at firstname.lastname@example.org
- Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379(9817):713-720.
- Advanced Cell Technology Achieves Clinical Milestone [press release]. Marlborough, MA. January 8, 2013.
- Rose S. There’s More than One Way to Correct a Genetic Defect. April 11, 2012. Available at: http://www.blindness. org/blog/index.php/2012/04/page/2/. Accessed January 17, 2013.