REGROWING RETINAS: By culturing mouse embryonic stem cells, researchers can grow nascent retinas containing photoreceptor precursors that express the visual pigment rhodopsin (green) and the transcription factor Crx (red) and can be isolated and transplanted into adult mice.IMAGE BY ANAI GONZALEZ-CORDERIn mid-June, Newark, California–based StemCells, Inc. announced interim results of its ongoing Phase 1/2 trial for the treatment of dry age-related macular degeneration, a form of progressive blindness common in the elderly. Seven patients with advanced disease who had been dosed with the experimental therapeutic—multipotent neural stem cells derived from fetal brain tissue—showed slowed retinal atrophy at one year post-transplant, and four had not just stabilized but improved visual function, the company reported.

“They’ve actually had gains in their visual ability to sense contrast, which is the difference between light and dark,” explains Stephen Huhn, the company’s chief medical officer and vice president for central nervous system...

StemCells’ announcement is the latest in a series of promising developments in the area of cell-based therapeutics for blindness. Advanced Cell Technology (ACT) has several ongoing trials based on differentiated cells derived from human embryonic stem cells (hESCs), and last year, Japanese researchers launched the first clinical study to use induced pluripotent stem cells (iPSCs) derived from adult human cells for the treatment of age-related macular degeneration. Still other strategies are in development, and excitement is high.

“I’ve been amazed at just how quickly the field has grown and how fast it has progressed toward clinical trials,” says David Gamm, an associate professor of ophthalmology and visual sciences and director of the McPherson Eye Research Institute at the University of Wisconsin School of Medicine and Public Health.

It’s still early days, he warns. While initial results are promising, that’s all they are at the moment. Nobody with blindness has yet been “cured” with a stem-cell therapeutic. And there are substantial safety issues to contend with when implanting live cells in the eye. “We’re pushing the boundaries of this technology,” Gamm says. “And as such, we expect there to be probably more bumps in the road than smooth parts.”

Why the eye?

The eye was not the first organ to receive transplanted stem cells. StemCells tested its cells in the brain and spinal cord before moving to the eye, and Geron, the first company authorized by the US Food and Drug Administration (FDA) to launch an hESC-based trial, targeted the spinal cord as well. (The company has since abandoned the field, selling its stem cell portfolio to BioTime subsidiary Asterias Biotherapeutics, which on August 27 announced it had received FDA approval to launch a new Phase 1/2a trial in 13 patients with spinal cord injury.) Other researchers are targeting the brain and spinal cord as well, not to mention the blood, pancreas, heart, and other nonneural tissues. A search of for “stem cell transplant” returns some 3,329 hits.

But for many stem-cell researchers and drug developers, the eye is the ideal organ for treatment with stem-cell therapeutics. It is small, and therefore requires relatively few cells for efficacy; and it is immune-privileged, meaning allogeneic (nonself) transplants may be used with little risk of immune rejection. Function is easily quantified in the eye, and even incremental improvements can yield large benefits for the patients.

As a practical matter, the eye is also the only part of the central nervous system (CNS) that is externally visible and accessible, and researchers can track transplanted cells noninvasively using techniques such as optical coherence tomography (OCT). Like a high-resolution optical version of ultrasound imaging, the technique provides “histological detail down to a micron or so resolution,” says Michael Young, associate professor of ophthalmology and codirector of the Ocular Regenerative Medicine Institute at Harvard Medical School. “That turns out to be, from a therapeutic point of view and from an endpoint-analysis point of view, a great tool for us in trying to figure out whether these things work or not, and secondarily, is something wrong.”

Another important advantage of targeting the eye, says Young, is safety. The eye is relatively self-contained and, disturbing as it may sound, nonessential. “Imagine a stem-cell transplant for Parkinson’s disease, where you inject stem cells into the middle of the brain, and something goes wrong. What do you do? The answer is nothing, you can’t do anything. In the eye, if something goes wrong, and in these early stages something can go wrong, you can actually remove the eye and remove the cells,” he says.

This is particularly important for therapies derived from hESCs or iPSCs, which, unlike adult stem cells, can divide indefinitely and differentiate into any cell type of the entire body. As such, they also pose a risk of tumorigenesis in transplant recipients should undifferentiated cells accidentally be introduced into a patient.

Providing new support

Though there are hundreds, if not thousands, of diseases that affect the eye, most cell therapeutic programs to date have focused on macular degeneration, “the commonest cause of sight loss in the Western world,” says James Bainbridge, a professor of retinal studies at the University College London Institute of Ophthalmology and the chief investigator of ACT’s UK-based trials. “We can all expect to develop it if we live long enough.” More than 2 million Americans were suffering from age-related macular degeneration in 2010, according to the National Eye Institute.

Macular degeneration involves the loss of retinal pigment epithelium (RPE) cells, which secrete growth factors, remove metabolic waste, and recycle the photopigment retinal that is required for the function of the adjacent rods and cones. “They’re basically a support cell for the photoreceptors,” says stem-cell biologist Dennis Clegg of the University of California, Santa Barbara (UCSB). As the RPE beneath the macula, or center of the retina, begins to deteriorate, the photoreceptor neurons begin to die as well, and central vision—critical for reading and writing, recognizing faces, and low-light vision, among other functions—is lost. (See illustration.) One way to halt disease, then, is to replace the RPE cells or provide a substitute to stem the continued degeneration of the photoreceptors.

StemCells’ HuCNS-SC transplantation works by supplementing a patient’s remaining RPE cell function with neural progenitor cells not normally found in the eye. Although derived from donated fetal brain tissue—“obtained through a nonprofit tissue procurement agency following an elective abortion,” according to Huhn—StemCells’ therapeutic is technically an adult stem-cell product, in that the cells have lost the pluripotency that defines embryonic stem cells. Neural stem cells extracted from the fetal brain tissue are expanded and cryopreserved; once thawed and implanted into patients, the cells can differentiate into neurons, astrocytes, and oligodendrocytes. “The broad category of mechanism of action is probably some type of neurotrophic effect,” Huhn says.

I’ve been amazed at just how quickly the field has grown and how fast it has progressed toward clinical trials.——David Gamm, McPherson Eye Research Institute, University of Wisconsin School of Medicine
and Public Health

Janssen Research & Development’s CNTO-2476, an allogeneic cell therapy derived from human umbilical cord tissue, is believed to secrete trophic factors that support diseased retinal tissue, according to a company spokesperson. The therapy has been tested in trials for age-related macular degeneration and retinitis pigmentosa, and a large, randomized trial for macular degeneration is being planned to further assess its efficacy and safety.

ACT’s strategy is more direct: supply new RPE cells to replace and repair the native RPE layer. ACT has initiated four Phase 1/2 trials testing its hESC-derived RPE therapy for the treatment of the dry form of age-related macular degeneration (dry AMD); a heritable form of the disease called Stargardt’s; and myopic macular degeneration, a form of vision loss caused by abnormal elongation of the eyeball. The company described its initial findings for the first dry AMD and Stargardt’s disease patients in a 2012 Lancet paper, with results pointing to the protocol’s safety and hinting at its efficacy (379:713-20). One patient, for instance, improved from 20/500 to 20/320 vision, which corresponded to a modest improvement in ability to read an eye chart, albeit with “mild visual function increases in the fellow [untreated] eye.” In 2013, ACT announced that one of the more recently treated dry AMD patients had experienced an improvement from 20/400 to 20/40.

These promising results, along with those from StemCells’ Phase 1/2 trial this summer, suggest that restoring or replacing RPE function can not only halt the spread of macular degeneration, but partially reverse it—essentially kick-starting photoreceptors that were dying but not yet dead.

UCSB’s Clegg and his colleagues at the nonprofit California Project to Cure Blindness and elsewhere are also pursuing the RPE approach. The team plans to transplant sheets of RPE cells derived from hESCs deposited on an artificial substrate called parylene, which mimics the extracellular matrix layer of the RPE. With $19 million in funding from the California Institute for Regenerative Medicine, the researchers hope to file an investigational new-drug (IND) application for dry AMD with the FDA by the end of the year, Clegg says.

Researchers at the RIKEN Institute in Japan have also announced plans to differentiate and transplant RPE cells for AMD, this time using iPSCs. The team, led by Masayo Takahashi, will generate iPSCs from patients’ skin cells, a process RIKEN says will take 10 months to complete. The cells will then be differentiated into 1.3 mm x 3 mm sheets of RPE cells and transplanted back into the patient the cells were taken from. If successful, the therapy would avoid the moral complications that accompany hESCs, which are created from human embryos. “There are a significant number of people who are not comfortable with ES cells,” says the University of Wisconsin’s Gamm.

Replacing photoreceptors

MIXING OLD AND NEW: When transplanted into the mouse retina, photoreceptors (green) derived from mouse embryonic stem cells integrate into the retinal network and contact the neighboring neuronal layer, the bipolar cells (red).IMAGE BY DR ANAI GONZALEZ-CORDEROOnce rods and cones are dead, however, even an infinite supply of RPE cells cannot help. To more fully restore vision in patients with retinal degeneration, researchers are looking to replace the photoreceptors themselves. This strategy is more complicated than the RPE approach, however. To be functional, photoreceptors must not only implant and survive, but extend neural processes and form synaptic connections with downstream bipolar neurons. (See photograph at right.) Fortunately, it’s a relatively short gap to fill, says Matthew Vincent, ACT’s Director of Business Development. “If you’re going to think about replacing a neuron with a stem cell, that’s probably the best one you could imagine doing.”

Preclinical work suggests the strategy can work. In 2012, researchers in Robin Ali’s group at University College London reported in Nature that transplanting murine photoreceptor precursor cells yields functional improvements in mice that lack rods (485:99-103). And while no photoreceptor-based strategy has yet entered clinical trials, several are in development.

Young’s group at Harvard Medical School, for example, is working on a strategy for treating retinitis pigmentosa that involves transplanting human fetal retinal progenitor cells, which develop into rods. Retinal progenitor cells, he explains, are proliferative cells that are “one stage less developed” than the precursor cells Ali used in his mouse study and are thus easier to grow. Furthermore, human retinal progenitor cells have been safely banked under good-manufacturing-practice (GMP) conditions and are ready for a future trial, Young says. He and his partners, including UK-based ReNeuron, will meet with the FDA later this year and hope to launch a clinical trial in early 2015.

ACT is also preparing to launch clinical trials based on hESC-derived photoreceptors, says Vincent, possibly also early next year. “I think the photoreceptor progenitors will likely be the next ‘IND-able’ . . . program for the company.”

Gamm, meanwhile, has worked out methods to differentiate iPSCs into photoreceptor precursors and other retinal cells, and is working with Clegg on a strategy for treating dry AMD that involves both RPE and photoreceptor precursors. But rather than deriving such cells from individual patients, as the RIKEN group is doing, Gamm and his colleagues figure that it will be less expensive and faster to bank a wide variety of HLA-typed iPSCs. (See “Banking on iPSCs,” The Scientist, September 2014.) “Similar to how you might get a close match, but not perfect match, for an organ transplant, we could do the same thing for all cell types derived from certain iPS [cell] lines,” Gamm explains.

To the clinic

As cell therapies make their way into the clinic, there’s one overriding concern clinicians and regulators have, says Gamm: “Safety, safety, safety.” Indeed, Geron, the first company to get an hESC-based therapeutic into clinical trials, submitted an IND application that was reportedly some 22,000 pages long—the largest ever approved by the FDA.

ACT, the second company to win IND approval for an hESC therapy, went to considerable effort to assure the FDA that the risk of tumor formation from its hESC-derived RPE cells was as low as possible—among other measures, developing a new proprietary method for detecting contaminating undifferentiated cells that is some five orders of magnitude more sensitive than PCR, says Vincent. “The first, second, and third issue for the FDA really was safety,” he said: “prove to us that there is no risk that these patients are going to develop tumors as a consequence [of] these cells that you’re injecting.” The company’s first IND took a year to get the nod, though subsequent applications were approved in less than one month each, he noted.

As these companies and researchers lay the groundwork, other players should have an easier time. (See “Stem Cells Off the Line,” The Scientist, April 2014.) Now, says Gamm, the challenge is managing expectations. At the moment, things are looking up for the field, and research is advancing rapidly. But at some point, he says, “we’re going to hit something that will take us a while to figure out.” Gamm says he tries to make that clear when talking to patients and disease foundations. Riffing on the customary disclaimer accompanying mutual fund literature, he says, “Past performance is not a guarantee of future progress.” 

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