Look to the retina as a likely site for the first success in stem-cell therapy.

"The eye is the best place to test proof-of-concept for stem cell-based therapies," says Martin Friedlander of the Scripps Research Institute in La Jolla, California. Friedlander is co-founder of EyeCyte, also in La Jolla, whose investors include industry heavyweight Pfizer.

Several laboratories are exploring stem-cell-derived transplants to delay or prevent blindness, and Pfizer recently put up funds for a project nearing human trials at University College London (UCL).

Why the eye appeal? As organs go, it is easily accessible, somewhat protected from the immune system's propensity for transplant rejection, and comes in a convenient pair — so that doctors can try experimental treatments on just one eye.

There is also a pressing clinical need: 37 million people worldwide are blind and 124 million more have poor vision1. Experiments in animals suggest that stem cell treatments in the eye are fairly safe, and researchers have maintained a reasonable level of vision in a rat model of degenerative eye disease.

The eye looks promising for stem-cell therapies Credit: Getty Images / Jessica Kolman

Researchers are tapping a variety of cell types to reinvigorate the cornea and retina. "This is an area that has a lot of competition, and there are a lot of different mousetraps out there," says David Gamm, a stem cell biologist at the University of Wisconsin, Madison.

At UCL, Pfizer is teaming up with the multi-center London Project to Cure Blindness to develop human embryonic stem (ES) cell derived transplants for people with age-related macular degeneration (AMD). "Hopefully, what we would try to do is save the vision to a point where at least you would be able to read and recognize faces," says Pete Coffey, an ocular biologist at UCL and director of the London Project.

The project will supply the scientific know-how, while Pfizer will bring its expertise in navigating the regulatory hurdles between the lab and the clinic. "Together, we believe we make a really good team," says Ruth McKernan, chief scientific officer at Pfizer's regenerative medicine unit in Cambridge, UK.

"It's noteworthy that a large company like Pfizer has taken a look at the situation and decided it's worth their while," Gamm says. Pfizer's interest carries weight: "They're no dummies."

Pfizer has also expressed interest in buying Intercytex, a company that is providing the London project with a stem cell line.

The advantages of the eye

"The nice thing with the eye is you've got that window in front so you can see what's going on at the back," Coffey says. Ophthalmologists already have the tools they need to observe the retina, from the simple slit lamp to sophisticated imaging techniques that can pick out structures at near-cellular level.

The eye is also sealed off from the immune system, shielded by the tightly linked epithelial cells of the blood–retina barrier. So even if the transplanted tissues are not an exact match for the patient, immunosuppressants might not be necessary to prevent rejection. But should anything go awry, doctors could remove the offending cells, or even take out the eye.

Hundreds of people have already received adult stem cell transplants to treat chemical burns or diseases that scar the cornea at the front of the eye. Doctors can biopsy and culture the natural stem cells at the edge of the cornea from the patient's other eye or from a cadaver cornea to repair the damaged one. Sixty to seventy per cent of patients experience improved vision, says Julie Daniels, a stem cell biologist at UCL's Institute of Ophthalmology. But the therapy is not yet commercially available. "There are still a lot of unknowns," Daniels says. Clinical trial design is hampered by the paucity of potential trial patients and differences in their eye conditions, as well as by the scarcity of cadaver donors. And Daniels is reluctant to subject control patients to a painful sham procedure that, without the stem cells, has little hope of success.

Now, many scientists are setting their sights on the back of the eye, where photoreceptor cells — rods and cones — in the retina sense light. Photoreceptors depend on the retinal pigmented epithelium lining the back of the eye to provide growth factors and to mop up cell fragments containing spent light-responsive pigments. If these trash collectors break down, waste builds up, photoreceptor cells die, and vision disappears.

Scientists are eyeing several diseases to treat with replacement retinal epithelial cells. AMD is the third most common cause of visual impairment worldwide, and the top cause in developed countries. In AMD the retinal epithelium at the macula — the center of the retina, responsible for discriminating fine detail — deteriorates. This disease, which predominantly affects people over 50, is likely to become more prevalent as baby boomers age. Treatments such as the anti-angiogenic drug Lucentis are available for the 'wet' form of AMD, in which new blood vessels leak fluid, but there is little doctors can do for the more common 'dry' form of the disease.

The number of people with another common malady, diabetic retinopathy, is also likely to rise along with the increasing incidence of diabetes. The disease is the result of damage, caused by high blood sugar, to the blood vessels that feed the retina.

A third condition that stem cell biologists are targeting is retinitis pigmentosa, the result of inherited abnormalities in the photoreceptors or retinal epithelium. People with retinitis pigmentosa slowly lose their sight, starting with night vision.

Several groups have shown that transplants of retinal pigmented epithelium can slow sight loss in a classic animal model of sight degeneration, the Royal College of Surgeons (RCS) rat. In these rats the retinal epithelium fails to ingest photoreceptor segments. In one study, transplanting retinal epithelial cells differentiated in culture from human ES cells enabled RCS rats to maintain a visual acuity twice that of untreated controls, and 70% that of a normal rat. By the time RCS rats are 100 days old, they normally have only one layer of photoreceptors, as opposed to 10–12 layers in normal animals; the treated RCS rats maintained 5–7 layers2.

The London Project to Cure Blindness is focused on treating AMD with a monolayer of retinal pigmented epithelium derived from human ES cells. Coffey plans to grow the retinal epithelium on a polyester membrane, and then transplant the patch into the eye during short-stay outpatient surgery. He doubts that matching immune markers between transplant tissue and recipient will be necessary. "One cell line, that's all — which would be phenomenal if it's right," he says.

Coffey and colleagues have transplanted retinal epithelium into rodents and pigs, but want to conduct a longer trial in pigs—six months to a year—before moving on to human subjects, to make sure the cells survive without causing problems. The aim is to start clinical trials by 2011, and Coffey hopes that by 2015 or so, any retinal surgeon would be able to order fresh retinal pigmented epithelium.

"The concept is great," Friedlander says. "But I think there are much better ways to do this." Friedlander suggests that induced pluripotent stem (iPS) cells cultured from the person who needs a transplant would be safer, because there is no chance of rejection. The blood–retina barrier isn't absolute, he notes, and could be compromised in a person with eye disease. "If you start shooting things into people's eyes that didn't come from them initially, you're going to cause trouble," he says.

Exactly how, or indeed if, the immune system will respond to a transplant of retinal epithelium is unclear. Most rodent studies, as well as corneal stem cell transplants in people, have included immunosuppressants. But in one study of 10 patients who received unmatched fetal retinal transplants, none received immunosuppresants, and none showed evidence of rejection3.

Another option, under development by International Stem Cell Corporation in Oceanside, California, is to start with stem cells derived from unfertilized human eggs. With half the genetic variation of other stem cells, "this vastly simplifies the process of donor matching," says Ken Aldrich, founder and chief executive of the company. He estimates that 50 to 100 cell lines would be sufficient to make tissue-type matches for the world's population, and the corporation is working on both corneal and retinal epithelial transplants.

The company Advanced Cell Technology (ACT), in Worcester, Massachusetts, was the first to report making retinal pigmented epithelial cells from stem cells4. The method is fairly straightforward, in part because neural lineages, and those of eye cell types in particular, are a sort of default pathway for stem cells, says Robert Lanza, chief scientific officer at ACT.

Starting with human ES cells or iPS cells, 'freckles' of retinal epithelium, dark-brown because of their pigment, appear in the culture dish. The researchers pick out the brown colonies and seed a new dish, which the replicating cells will fill before they darken again. These derived retinal epithelial cells make many of the same proteins as the natural epithelium, and also share the ability to ingest extracellular material. "You can throw in little latex beads and they'll eat them," Lanza says.

ACT, however, plans a somewhat different clinical approach from the London Project to Cure Blindness. Instead of fixing the cells to a membrane, they intend to inject a suspension of cells in solution and let the cells find their proper position.

The best way to deliver new retinal epithelial cells is an open question. "It's important to get them in the right place," says Dennis Clegg, a stem cell biologist at the University of California, Santa Barbara. Only one face of the epithelium gobbles cell fragments, so that side has to be pointed towards the photoreceptors.

For some therapies, a suspension of stem cells will probably be sufficient to support struggling photoreceptors. Friedlander has shown that bone marrow-derived stem cells target and repair the blood vessels at the back of the eye5. "It's frickin' remarkable," he says. "These cells know where to go." EyeCyte is developing his work as a cellular therapy for diabetic retinopathy. Similarly, StemCells in Palo Alto, California, is betting on fetal neural stem cells to migrate to the retina and secrete molecules that help photoreceptors survive.

Photoreceptor replacement

Therapies based on retinal pigmented epithelium are aimed at preventing deterioration of rods and cones. But some researchers are working on replacing the photoreceptors themselves using neural stem cells. "That would be the Holy Grail," Clegg says. Such therapies — which could potentially restore lost sight — could reach human trials as early as 2012, says Michael Young, a neuroscientist at Harvard Medical School in Boston.

Of prime importance, numerous preclinical animal experiments have shown no evidence that stem-cell derived RPE and photoreceptor precursors transplanted into the eye formed teratomas. "You don't want a tooth growing in your eye," Aldrich says. However, eye tumors from transplanted neural precursor cells derived from ES cells have been observed in mice6, so in early human trials, safety will be paramount.

"If you don't really cross your t's and dot your i's, that could set the field back in a lot of ways," Gamm says. He points out that the development of leukemia in patients who received gene therapy for an immune disease impeded all gene therapy projects.

But successful clinical trials using stem cells to alleviate blindness would have an equally positive impact. "If they go well, it will accelerate everyone else's approach," Gamm says.