January 2005 - University of Florida stem cell scientists reported this January 3rd that they have prevented blindness in mice afflicted with a condition similar to one that robs thousands of diabetic Americans of their eyesight each year.
Writing in the current issue of the Journal of Clinical Investigation, researchers describe for the first time the link between a protein known as SDF-1 and retinopathy, a complication of diabetes and the leading cause of blindness in working-age Americans.
Scientists explain how they used a common antibody to block the formation of SDF-1 in the eyeballs of mice with simulated retinopathy, ending the explosive blood vessel growth that characterizes the condition.
Researchers effectively silenced SDF-1's signal to activate normally helpful blood stem cells, which become too much of a good thing within the close confines of the eyeball.
"SDF-1 is the main thing that tells blood stem cells where to go," said Edward Scott, an associate professor of molecular genetics at the UF Shands Cancer Center and director of the Program in Stem Cell Biology and Regenerative Medicine at UF's College of Medicine. "If you get a cut, the body makes SDF-1 at the injury site and the repair cells sniff it out. The concentration of SDF-1 is higher where the cut occurs and it quickly dissipates. But the eye is such a unique place, you've got this bag of jelly -- the vitreous -- that just sits there and it fills up with SDF-1. The SDF-1 doesn't break down. It continues to call the new blood vessels to come that way, causing all the problems."
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Diabetic retinopathy causes 12,000 to 24,000 cases of blindness each year, according to the American Diabetes Association. What happens is high blood pressure and blood sugar levels associated with diabetes cause leaks in blood vessels within the eye and hinder the flow of essential chemicals. The eye compensates by growing new blood vessels, which clog the eye and cause even more leaks. Damage occurs to the retina, gradually destroying its ability to capture images.
UF researchers analyzed samples of the vitreous gel taken from the eyeballs of 46 patients undergoing treatment for diabetic eye disease, including 24 patients with retinopathy. They found SDF-1 in each of the patients, with the highest amounts detected in patients with the worst cases. No traces of SDF-1 were found in the vitreous samples of eight nondiabetic patients who were treated for other ailments.
With the hypothesis that SDF-1 is at the heart of the problem, scientists tested to see whether the addition of the protein would call stem cells and spur extraordinary blood vessel growth in the eyeballs of 10 laboratory mice. They succeeded, creating mice with retinopathy-like conditions. Then, as a treatment, scientists injected an SDF-1 antibody directly into the afflicted eyes. The antibody -- which is simply another protein that binds to the SDF-1 -- disabled SDF-1's ability to summon stem cells, effectively halting the growth of almost all new blood vessels, said Jason M. Butler, a graduate student in the Interdisciplinary Program in Biomedical Sciences and a member of the research team.
Scientists next want to test the technique in monkeys, and if it continues to be successful, to test the therapy in human clinical trials, said Scott, the senior author of the paper. The National Institutes of Health funded the research in mice. The study in primates will involve support from RegenMed, an Alachua, Fla.-based company founded by Scott and other UF researchers to bring biomedical therapies to the marketplace.
"The scientific community and pharmaceutical companies have a long track record of being able to develop antibody-based therapy in things like snake anti-venoms," Scott said. "This isn't a new and unproven technology. This is something that can be rapidly adapted and brought to market."
Scientists said they still need to find a way to anchor the antibody to a molecule large enough so it can do its SDF-1-blocking work in the vitreous but will be unable to penetrate the retina. They envision a therapy that will involve routine injections of the substance into a patient's eye.
"It could potentially be a treatment option," said Dr. Maria Grant, a professor of pharmacology and therapeutics in UF's College of Medicine who participated in the research. "Current therapy for severe diabetic retinopathy is use of lasers that destroy parts of retina that are not needed for precise vision in order to improve oxygen delivery to the parts of the retina that are needed for detailed vision. Intraocular delivery of agents that block SDF-1 represent an excellent and less destructive alternative."
The research sheds light on the mechanisms of diabetic retinopathy and the various functions of SDF-1, said Nadir Sheibani, an assistant professor of ophthalmology and visual science at the University of Wisconsin-Madison Medical School.
"Many factors are at work during retinopathy and it's important to understand each of them," Sheibani said. "It's interesting that the researchers show how SDF-1 changes the levels of a protein called occludin, which affects junctions between cells that line the blood vessels. It helps explain why the blood vessels become leaky and edema develops during diabetic retinopathy."
Source: University of Florida
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