The stem cell community recorded something of a milestone this past month. Researchers at Advanced Cell Technology, with colleagues at the University of California, Los Angeles, became the first to publish peer-reviewed data on the use of a human embryonic stem cell (hESC)-derived cell therapy in the clinic.
The findings are only preliminary, detailing a four-month follow-up safety and efficacy assessment of just two patients treated with a single low dose of cells, and much remains to be done before the medical promise of stem cells can truly be realized. Yet the fact remains that at first blush, the therapy appears to be both safe and somewhat effective – though the possibility of a placebo effect cannot be discounted.
The team reported in The Lancet preliminary findings in two patients with retinal degeneration, one with “dry” age-related macular degeneration (AMD), the other with Stargardt's macular dystrophy, who were treated with subretinal injection of 50,000 hESC-derived retinal pigment epithelial (RPE) cells. 
The eye is a popular and sensible initial target for stem cell therapy, says Michael Young, an associate professor at the Schepens Eye Research Institute at Massachusetts Eye and Ear, Harvard Medical School, and Affiliate Faculty member of the Harvard Stem Cell Institute (HSCI). It is small, meaning few cells can potentially have a big impact, and also confined, such that injected cells are unlikely to migrate to other tissues. As the body’s only transparent organ, the eye is easily and noninvasively imaged, and because there are two of them, researchers have a built-in control for their studies. Plus, the eye is relatively immunoprivileged, a bonus when the therapeutic material comprises foreign cells.
But perhaps most importantly, the eye represents an attractive target because of the substantial quality of life gains even a modestly effective therapeutic can offer. “Just giving somebody back some level of visual perception, some level of light detection even, when they had none — that kind of thing is very important, I think,” says Young.
In this case, the researchers chose to focus on two forms of macular degeneration. AMD is “the leading cause of blindness in the developed world,” the authors note, while Stargardt’s “is the most common paediatric macular degeneration.” The macula is a concentrated region of photoreceptors at the center of the retina. Pigment epithelial cells form a layer of cells in the eye that support and nourish those photoreceptors by, among other things, recycling photopigments and removing waste products. If those cells die (as they do in AMD and Stargardt’s disease), the photoreceptors eventually die, too.
The two patients were enrolled in a pair of Phase I/II clinical trials for which safety was the primary outcome, and on that front the authors report positive results: none of the usual stem cell-related concerns — cell proliferation, teratomas, immune rejection, and inflammation — were observed, they write. (ACT declined to be interviewed for this article.)
The presence of implanted cells could be verified in only one of the two patients post-implantation. Yet the authors report apparent efficacy in both. One patient improved from 20/500 vision to 20/320 in six weeks; the other improved from seeing only “hand motions” to 20/800 vision. But, the authors concede, it isn’t possible from these data to know whether those gains are due to the cellular therapeutics themselves, the immunosuppressants the patients took to prevent rejection, or the placebo effect.
As the first peer-reviewed report demonstrating the use of hESC-derived therapeutics, the study provides something of an experimental roadmap for other stem cell researchers to follow — “a good description of the treatment modality, how it was performed, and how the patients did in the short-term,” says Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine, who wrote a commentary accompanying the report. 
But the data are only preliminary, he and others stress, and how the cells and patients will fare long-term remains to be seen. HSCI member George Daley, Director of the Stem Cell Transplantation Program at Children’s Hospital Boston and Executive Committee member and Principal Faculty at the Harvard Stem Cell Institute, notes, for instance, that the paper details the experience of just two patients over four months — patients who were aware of the treatments being done (the trials were not blinded) and highly motivated to anticipate good outcomes.
The milestone, Daley explains, “is getting through the very rigorous regulatory process” — convincing the US Food and Drug Administration that the cells should be safe, administering those cells in humans, and then showing that they are, in fact, actually safe, albeit in only two patients. But, he adds, “It’s going to be a long time before we really learn enough about how to deliver the products at the right dose, in the right place, and get them to do what they’re supposed to do in order to know that they’re effective.”
Dennis Clegg, co-director of the Center for Stem Cell Biology and Engineering at the University of California, Santa Barbara, echoes the point. “You’re really talking about a very early, n equals 1 experiment, and we have to allow more time and more studies to determine if the treatment is truly effective.”
In the meantime, other researchers are pursuing alternative strategies towards the same goal.
Young and Daley, for instance, have shown that subretinal transplantation of “photoreceptor precursor cells” derived from adult mouse iPS cells, can produce functional photoreceptors in vivo. Unlike RPE cells, photoreceptors are neurons. As they are more fragile than RPE cells, and must form synaptic connections to be functional, they represent a more challenging therapeutic, says Clegg. Nevertheless, when Young and Daley implanted their cells in a mouse model of retinal degeneration and stimulated them with light, the implanted photoreceptors fired 21 days post-implant, whereas cells in the contralateral eye did not. 
According to Young, his team opted to transplant photoreceptor progenitors rather than RPE cells, because RPE cells only maintain the photoreceptors, but cannot replace them. Some visual disorders, such as retinitis pigmentosa, cannot be repaired with RPE cells, because the problem lies with the photoreceptors themselves. “You can put in all the RPE cells you want,” he says, “you cannot restore function because the photoreceptors don’t regenerate.” The team is already mass-producing these human cells under GMP conditions, Young says, in anticipation of entering clinical trials.
Deepak Lamba, assistant professor at the Buck Institute for Research on Aging, with his then-postdoc mentor Thomas Reh of the University of Washington, achieved similar success when they transplanted hESC-derived photoreceptor progenitors into a mouse model of Leber’s Congenital Amaurosis, an inherited form of retinal degeneration that results in blindness in early childhood.  The cells partially repopulated the photoreceptor layer in this study, and as measured by electroretinography, produced an electrical spike in response to light two or three weeks later. The question now, Lamba says, is whether and how that actually translates into visual improvement. “We don’t know how the brain responds to these cues,” he says.
The California Project to Cure Blindness (thecaliforniaproject.org) is pursuing yet another strategy. According to Clegg, who is a member of the Project, it, like ACT, is pursuing RPE cells. But while ACT implanted “a bolus injection of dissociated cells,” the Project is developing methods to grow and implant them in a synthetic substrate as a polarized monolayer, as they normally exist in vivo — a sheet of cells with distinct basal and apical faces, “like a contact lens coated with cells that would be implanted in the back of the eye,” he says.
Clegg says the California Project hopes to file an IND application with the FDA by 2014. (A related project, the London Project to Cure Blindness has announced plans to initiate human trials of its hESC-derived RPE therapy, in collaboration with Pfizer, some time in 2012.)
Meanwhile, on Feb. 2 StemCells Inc. announced it had received FDA approval to initiate a Phase I/II clinical trial of its stem cell therapy, called HuCNS-SC®, in dry AMD. HuCNS-SC cells are adult neural stem cells; they do not originate from hESCs or iPSCs, and do not normally exist in the adult eye. But these cells have already undergone clinical testing in trials involving a lysosomal storage disorder, a myelination disorder, and spinal cord injury. To date, a total of 22 patients have undergone transplantation with HuCNS-SC in these three trials combined. Data from those trials (only one of which is completed) indicate that the cells present “a favorable safety profile,” says Stephen Huhn, the company’s vice president for CNS programs. The new trial in dry AMD will enroll up to 16 more.
According to Huhn, HuCNS-SC cells are not intended to replace a missing cell population. That differentiates them from the strategies employed by ACT, the California Project, and others. Instead, these cells are simply neuroprotective, nurturing the photoreceptors via different mechanisms, one of which may be the release of cytokines and growth factors. “Biologically, you’re not swinging for the fences and trying to replace photoreceptors,” Huhn says. “What you’re going to do is put in a cell that will by its presence protect and preserve the host photoreceptors and hopefully effect an impact on vision.”
How these or any other therapeutic regimen for retinal degeneration will pan out, is an open question. As Atala put it in his Lancet commentary, “Much remains to be seen — literally.”
 S.D. Schwartz et al., “Embryonic stem cell trials for macular degeneration: A preliminary report,” The Lancet, DOI:10.1016/S0140- 6736(12)60028-2, published online Jan. 23, 2012.
 A. Atala, “Human embryonic stem cells: Early hints on safety and efficacy,” The Lancet, DOI:10.1016/S0140- 6736(12)60118-4, published online Jan. 23, 2012.
 B.A. Tucker et al., “Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice,” PLoS ONE, 6:e18992, 2011.
 D. Lamba, J. Gust, and T. Reh, “Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice,” Cell Stem Cell, 4:73—9, 2009.