DEC 2013

EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.

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50 EW RETINA December 2013 Reeling in first success with synthetic rod transplantation by Maxine Lipner EyeWorld Senior Contributing Writer Casting for new ways to cure blindness I magine being able to cure blinding conditions such as age-related macular degeneration and diabetic retinopathy simply by replacing lost photoreceptors with those from a dish. That's the direction new research is heading, according to Robin R. Ali, PhD, FMedSci, professor of molecular genetics, University College of London. Recent study results from the August issue of Nature Biotechnology show it is possible to successfully transplant rod cells grown on a synthetic retina from embryonic stem cells to visually impaired adult mice, Dr. Ali reported. "Of patients with registered blindness, the majority are ultimately due to a loss of photoreceptors," he said. "In age-related macular degeneration, in diabetic retinopathy and in inherited retinal degenerations, it's the loss of photoreceptors that causes blindness." Currently once photoreceptors are lost the only available treatment is use of an implant such as the Argus II retinal prosthetic (Second Sight, Sylmar, Calif.). In such cases, patients with no light perception are given the implant and receive input from a photosensitive diode, Dr. Ali explained. However, he pointed out that with this approach the amount of resolution is limited. "If you think of the retina as a digital camera the number of pixels would be megapixels, and with retinal implants there would be a few hundred at most," he said, adding this allows for only some perception of major shapes. Baiting a new hook While some are trying to improve such resolution, Dr. Ali's team has taken a different tack. "Our approach is to replace the photoreceptors, and our hypothesis is that we'll be able to do that more effectively than engineering a retinal implant because we have less of an issue with biologic compatibility," Dr. Ali said. Also, the resolution will likely be better since his team is able to transplant tens of thousands of photoreceptors with their approach. Dr. Ali's early work in the area involved taking rod cells from an immature mouse retina and transplanting those into visually impaired adult mouse retina. The donor photoreceptors were taken from postnatal mice that were just a few days old, he explained, adding that in mice the retina is still developing after birth. "We found that photoreceptor cells have to be at a particular stage of development to incorporate successfully," he said. Unfortunately, in humans the equivalent stage would be to take photoreceptors from a third trimester fetus, which of course would not be feasible, Dr. Ali said. A renewable source of such cells was needed. Investigators looked to transplanting rod cells from a synthetic retina. "What's exciting about this work is that it builds on a breakthrough by a Japanese group in which they developed whole retinas in a dish from embryonic stem cells," Dr. Ali said. "We've adapted that approach." The technique entails taking embryonic stems cells and culturing these in a dish in a 3D jelly-like matrix. An entire retina forms over a few weeks, Dr. Ali said. "The 3D (jelly) provides a scaffold and it allows self-assembly of the cell," he said. "We add a few growth factors, but we're not instructing it in a precise way—somehow the retinal cells know how to organize themselves." Investigators found the exact time point to take the photoreceptor cells from the dish to transplant Nascent retinae generated from 3D embryonic stem cell cultures. The retinae contain photoreceptor precursors that express normal photoreceptor proteins, including the visual pigment, rhodopsin (green), and the phototransduction enzyme, recoverin (red). The precursors from such retinae can be isolated and transplanted into adult mice. Source: Anai Gonzalez-Cordero, PhD them effectively. While they still can't do this as effectively as immature photoreceptor cells from a young mouse donor, it is a matter of further optimization, Dr. Ali said. Netting results Although there is room for improvement, the rod transplant was successful. "We could show that they migrated and integrated into the host retina and made connections to the bipolar cells, the next-order neurons within the retina," he said. However, based on this study, investigators can't say with certainty whether they could restore vision, since too few cells were transplanted. Yet other research gives Dr. Ali reason to be optimistic. "We published a paper in Nature (May 2012) in which we showed that we could improve vision in a mouse with photoreceptor transplantation if we get a sufficient number of cells into the retina," he said. "We're confident that if we had increased numbers we'd see the same effect because the cells are indistinguishable and behave just the same as endogenous photoreceptors taken from a donor mouse." The same technique can be used for other retinal cells, he said. "So far we have shown that it is effective for rod photoreceptors, and we've shown that the same principle applies to cones but is less efficient for cones," he said. The same, however, has not been true for other retinal cells. "There is something special about the way the rods and cones are able to migrate," Dr. Ali said. There is also some work being done on using retinal pigment epithelial cells to try and ameliorate diseases such as AMD and Stargardt's. However, because of the loss of photoreceptor cells in such conditions, Dr. Ali doubts that retinal pigment epithelium (RPE) transplantation alone is likely to be successful in most cases. "I think it is something that one might consider in tandem with photoreceptor replacement," he said. Dr. Ali views his own latest study on rod transplantation as another proof of concept that photoreceptor transplantation might be an effective clinical strategy. "What's important about this latest study is it shows that we can do this using a renewable cell source—an embryonic stem cell-derived source," Dr. Ali said.

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