stem cell

Stem Cell Research and the Eye

Dry AMD and Stargardt's targeted by new trials. Here's what you and patients should know.

Frank Celia, Contributing Editor

Because the retina is the only part of the central nervous system accessible non-invasively, eyecare presents a natural starting point for stem cell therapy trials. The retinal pigment epithelium (RPE), located at the base of the retina, provides crucial support and nourishment to the photoreceptors. But it is also frequently the site of disease and aging. In fact, RPE degeneration has been associated with some 200 different maladies—the majority incurable.

“When you talk about unmet medical needs, eyecare stands out,” says Matthew Vincent, Ph.D., director of business development for Advanced Cell Technology (ACT), Inc. (Santa Monica, Calif), a biotechnology company that applies cellular technology in the field of regenerative medicine. “Other than wet AMD, there really is no other form of macular degeneration in which treatment has advanced—up until now, potentially.”

Earlier this year, Dr. Vincent's company gained FDA approval to begin prospective trials on small cohorts of patients who have dry AMD and Stargardt's macular dystrophy. The studies are two of only three embryonic stem cells trials the agency has green-lighted so far (The third involves patients who have spinal cord injuries.)

Though the trials and the enormous medical potential of these therapies have generated great excitement, they have also given rise to scam artists out to swindle credulous patients.¹ Furthermore, ethical debates continue to complicate embryonic stem cell therapy, and a pending legal challenge could jeopardize government funding.

At the very least, however, optometrists should be familiar enough with these would-be treatments to dispel rumors and educate patients. A primer on stem cells and their visioncare potential follows.

Confocal microscopic images of retinal sections in an animal model (rat) double stained with recoverin (green) and PKCa (red) in a preclinical trial. (Green staining shows the photoreceptor layer.) The control group (right) didn't receive the retinal pigment epithelial (RPE) cells treatment (batches of RPE-derived from NIH-approved human embryonic stem cells). The treated group, (left), however, experienced a slowing in the progression of retinal dystrophy.

Cell self-renewal

A stem cell has the capacity for self-renewal and the ability to differentiate into multiple, mature cell types. Classically, stem cells are divided into adult (or somatic) and pluripotent (usually embryonic). Adult stem cells exist in many different tissues of the human body, providing lifelong repair and cell renewal. The most commonly cited example of adult stem cells are the hematopoietic ones located in bone marrow, which continually replenish our blood supply. Limbal cells of the corneal epithelium represent another relevant example. Adult stem cells typically are multipotent—that is, they can only differentiate into a limited number rather than a full range of mature cells. Therapies involving adult stem cells occur commonly in medicine. For years, visioncare patients with severe corneal disease have received limbal stem cell transplants from a healthy fellow eye or a sibling's eye.

Embryonic stem cells (ESC), on the other hand, are pluripotent, meaning they have the potential to develop into any cell that exists in the human body. This characteristic gives ESCs much more power and versatility than adult stem cells. Human ESCs are derived from the inner cell mass of a newly formed embryo, known as a blastocyst. Previous methods of generating ESCs destroyed the embryo from which cells were harvested, but more recent methods allow for extraction of only a single ESC without ablating the embryo.² This harvesting technique resembles the preimplantation genetic diagnosis commonly performed during in vitro fertilization efforts.

Steven Schwartz, M.D., the ACT studies' principal investigator and retina division chief at UCLA's Jules Stein Eye Institute, transplants the fully differentiated RPE cells derived from human embryonic stem cells in a human patient's eye.

A few years ago, researchers discovered that embryos are not the only source of pluripotent stem cells. A new technique allows for the generation of pluripotent stem cells without involving embryos at all. Using any adult human cell, say a skin fibroblast, researchers are now able to reprogram the cell into a so-called induced-pluripotent stem cell (iPSC)—a discovery quickly hailed as revolutionary. Not only did this preclude the ethical conundrums associated with embryo use, it opened the door for creating replacement organs from patients' own genetic material, thus circumventing the age-old problem of donor tissue rejection. As an example, a practical iPSC technology would obviate the most common reason for penetrating keratoplasty failure. Enthusiastic news stories about this type of stem cell generation continue to appear in the lay media.

Unfortunately however, it looks like iPSCs in their current state fall short of researchers' highest hopes. When compared with embryonic cells, they demonstrate higher rates of cell death, or apoptosis, and their proliferation rates have proven far lower than anticipated.³ Though iPSCs may still offer great potential, related therapies are probably years away from reality. In the meantime, many investigators have turned their attention back to embryonic stem cells.

Current eyecare trials

Based at the Jules Stein Eye Institute in Los Angeles, ACT's Phase I/II trials aim to use RPE cells derived from human embryonic stem cells to replace the diseased RPE cells before their function is lost. Subjects have begun receiving subretinal injections of stem cells that already have differentiated into RPE cells. Each of the two studies include 12 patients with either Stargardt's macular dystrophy or dry AMD. Each study will divide the subjects into four groups who will then receive escalating dosages of the therapy.

Cancer risk is a big concern surrounding stem cell therapy. Cells entering the body that are not fully differentiated pose the risk of developing into tumors. Thus, proving no undifferentiated or partially differentiated cells would enter the body was a major criterion for FDA approval of the study.

“I can't say there is no risk whatsoever of tumor formation, but I can say the risk is vanishingly small,” says Dr. Vincent. “What we inject into the eye is a fully differentiated retinal pigment epithelial cell suspension.”

After ACT developed and demonstrated a new method for testing suspensions for contamination, FDA officials allowed the study to move forward, according to Dr. Vincent.

Dr Vincent says his company's next FDA application, probably within the next year, will most likely be for a similar cell suspension aimed at treating myopic macular degeneration.

Patient education

Given all the attention the lay media is paying stem cell therapy, it probably won't be long before patients begin to inquire about it. Indeed, if your patient population includes a high percentage of seniors, you may already have fielded questions.

“I've had some patients within the last couple of months ask about stem cell therapy for retinal disease,” says Steven Ferrucci, O.D., F.A.A.O., chief of optometry at Sepulveda VA Ambulatory Care Center & Nursing Home, in Sepulveda, Calif. “Apparently a piece on the news somewhere mentioned one of the new studies.”

Patients are understandably excited about potential new therapies, but Dr. Ferrucci says he sees his role as someone who tempers unrealistic expectations. In other words, patients must understand these studies are in their earliest stages, he says. Even if proven viable, treatments are at the very least five years away. Unfortunately, stem cell therapy may not arrive in time to help current macular degeneration patients, he adds.

It is also important to warn patients about scam artists, who are increasingly using the phrase “stem cell therapy” to hawk fraudulent miracle cures, says Dr. Ferrucci. Stories abound of patients duped into traveling overseas at great expense on “stem cell tourism” junkets. A convenient rule of thumb, advises Dr. Ferrucci: Avoid clinicians who ask for large sums of money before seeing a patient or conducting an examination.

Ethics

Profound ethical concerns have plagued embryonic stem cell research, raising deeply divisive questions that extend way beyond the boundaries of the medical community—touching on politics, religion and matters of life and death. (See “Stem Cell's Government-Funding Saga,” image below.) The stem cell public funding issue has played a significant role in the last two presidential elections. Yet, despite all the debate, difficulties remain far from resolved.

To many it might appear the confirmation in 2008 of a harvesting technique that left embryos intact settled matters. But the issue is not so simple, authorities say. Some studies have found that harvesting cells from an embryo slightly reduces its chance of being successfully fertilized in vitro and carried to full term. This technique, called single-cell blastomere biopsy, has generated controversy. “You just can't know that you are not bringing harm to an embryo,” argues Father Thomas Berg, executive director of the Westchester Institute for Ethics and the Human Person, a Catholic think tank.⁴

Stem cell therapy proponents call such arguments faulty. To start, the studies on which they are based are not conclusive, they say. Also, the embryos in question are invariably leftovers donated by couples undergoing in vitro fertilization and are, therefore, destined for the medical wastebasket or indefinite freezer storage, proponents say. “If you look at what's going to happen to these embryos, the intervention of the stem cell step doesn't really change anything,” says Ronald M. Green, Ph.D., a professor of ethics at Dartmouth College, in Hanover, N.H., and chairman of ACT's Ethics Advisory Board. He adds that freezing itself is known to reduce the chances of embryo fertilization.

For a time, it appeared successful iPSC lines would resolve the debate. But, even they would present challenges, practitioners say. “Rather than avoiding ethical controversy altogether, researchers working with iPSCs will be effectively trading one set of ethical concerns for another,” says Joseph J. Pizzimenti, O.D., associate professor, Nova Southeastern University, Fort Lauderdale, Fla., and Optometric Retina Society member. He cites the question of how to deal with incidental findings that may impact a living donor's health and the extent to which donors would retain rights to downstream research. Should donors be informed if they carry genetic mutations that could lead to disease? If their cell lines are used to cure other conditions, do they deserve financial compensation?

Most advocates of stem cell therapy believe these ethical debates will swiftly end once a positive outcome emerges. Dr. Green says: “ … When the first Stargardt's youngster recovers vision, only the most unreasonable and extreme people will continue to hold out against it.” OM

1. Zarzeczny A, Rachul C, Nisbet M, Caulfield T. Stem cell clinics in the news. Nat Biotechnol. 2010 Dec;28(12): 1243-6.
2. Chung Y, Klimanskaya I, Becker S, et al. Human embryonic stem cells lines generated without embryo destruction. Cell Stem Cell. 2008 Feb 7;2(2):113-7.
3. Choi CQ, Cell-Off: Induced pluripotent stem cells fall short of potential found in embryonic version. Scientific American. Feb., 2010:16.
4. Carter LS. Getting to the root of stem cell science. Dartmouth Medicine magazine. Fall, 2007:20-21.