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See Inside March 2007

Sight for Sore Eyes

Progress in cell transplants to heal damaged retinas
RETINA



EYE OF SCIENCE Photo Researchers, Inc.
Millions of photoreceptor cells residing in the human retina gather light and transmit signals to the brain. When these light-collecting cells die, they take the person's sight with them. Medical researchers hoping to reverse blindness have turned their gaze toward stem cells, and recent experiments have shown that these cells could replace photoreceptors lost in macular degeneration.

As the most common form of blindness, macular degeneration affects 10 percent of Americans older than 65 years. It first targets a protective lining called the retinal pigment epithelium (RPE), which shuttles nutrients to the photoreceptor cells and is vital for their survival. A transplant of fresh RPE tissue could rescue dying photoreceptors. But the approach is not feasible considering the large amounts of tissue needed to treat the millions of Americans who show signs of early macular degeneration.

Scientists at the biotechnology firm Advanced Cell Technology in Worcester, Mass., have generated a more abundant source of RPE cells. In 2004 they devised a way to coax embryonic stem cells to turn into transplantable RPE tissue. In a follow-up experiment, they injected the transformed cells into the eyes of rats that had a photoreceptor-killing genetic defect in their RPE cells. As the researchers reported in the September 2006 Cloning and Stem Cells, weeks later, when the effects of the disease would have normally set in, the rats receiving the treatment were able to track stripes on a rotating cylinder twice as well as those that did not. Their vision, though improved, was still far below normal.

But treating patients who have advanced degrees of macular degeneration or other photoreceptor diseases will ultimately require repairing the photoreceptor cells themselves. Last November researchers at University College London and other institutions announced that they had extracted cells from mouse retinas that were at different developmental stages and successfully transplanted them into blind mice. They found that immature photoreceptor cells from healthy newborn mice, rather than embryonic or adult mouse cells, migrated to the correct region of the retina and continued to develop into mature photoreceptor cells. The pupils that received these cells were also more sensitive to light than those that did not receive the transplant.

These findings have suggested the development stages at which to transplant cells--for instance, photoreceptor cells need to be relatively more mature than stem cells, according to Thomas Reh, who studies retinal development at the University of Washington. The human equivalent to the mouse cells, however, would have to be isolated from fetal retinas, posing the familiar problem of finding a source for the immature cells. Adult stem cells and cornea stem cells are two other possible sources for generating immature photoreceptor cells.

In his lab, Reh coaxes human embryonic stem cells into retinal stem cells, and currently about 6 percent of them subsequently turn into photoreceptor cells. That yield may sound small, but a low percentage is not necessarily discouraging, according to Evan Snyder, a stem cell researcher at the Burnham Institute for Medical Research in La Jolla, Calif. By studying what pushes those 6 percent into their fate as photoreceptor cells, researchers might figure out how to generate a larger number of transplantable cells. They might also come up with a way to select the right cells out of a mixed population; Anand Swaroop, an ophthalmology researcher at the University of Michigan at Ann Arbor, is working on a way to identify and weed out the photoreceptor cells by focusing on proteins present on cell surfaces.

Having generated a cell source and overcome the safety concerns associated with transplanting stem cells, researchers still face possibly their biggest challenge: showing that the transplanted photoreceptors wire up to other neurons that eventually connect to the optic nerves. Each photoreceptor must make hundreds of critical connections. "Just because you have the right cell type doesn't mean you have the right circuitry," Snyder says. The immature photoreceptors transplanted from mouse retinas show activity, but Swaroop cautions that behavioral tests must determine that the photoreceptor cells are being repaired. A partial connection could generate the activity seen in the mice's pupils, but true vision improvement depends on the animals' ability to react to color and other visual cues. Seeing, after all, is believing.

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