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Discovery by University of Utah researchers may help prevent blindness

SHARE Discovery by University of Utah researchers may help prevent blindness

University of Utah researchers have found that activating a protein that stabilizes blood vessels reverses diabetic retinopathy and age-related macular degeneration — two common causes of blindness.

They believe the treatment, which they tested in mice, may portend good news for many other diseases as well that occur or worsen because of vascular instability and leaky vessels.

The study, which involved several institutions, was published Sunday in Nature Medicine online.

While the research is several years from human use, the director of the U.'s John A. Moran Eye Center, Dr. Randall J. Olson, called the finding "historic" in a release about the study. Hemin Chin, director of ocular genetics at the National Eye Institute, termed it "a major scientific advancement."

"All major eye diseases are caused by blood vessels that are destabilized such that they leak or grow too much," said Dr. Dean Li, the study's senior author, who is a physician, geneticist and professor of internal medicine at the U. "The two major eye diseases that affect the United States are diabetic eye disease and age-related macular degeneration (AMD). The vessels start falling apart, leaking and bleeding, and cause you to go blind."

The newly discovered pathway antagonizes that process and the vessels stabilize, offering hope for treatment, prevention and possibly a cure.

Researchers activated a protein called Robo4 in mice in which they had simulated the eye diseases. The Robo4 stopped abnormal blood vessel growth and stabilized the vessels so they wouldn't leak — the primary causes of both types of eye disease.

Robo4 is found only in cells on the inside surface of blood vessels. When a protein called slit activates it, the process begins to stop leakage and inhibit undesirable growth.

Blood vessels have a receptor on the cell surface, and there are proteins that bind to it. By turning on a signal in the endothelium, Li said, "we tell the vessels to have a stable structure, to have good interactions with other cells so they don't leak." They've shown "proof of principle" in the eye with "well-worked-out models."

Many other illnesses also spring from or are greatly worsened by blood vessel instability and leakage. With SARS or influenza, for instance, infection causes unstable blood vessels to leak fluid into the lungs. Blood vessels are also central to tumors, which feed off blood vessels. Whether turning on Robo4 would treat those and other ills is unknown, but Li is hopeful.

"What our discovery does has direct application to eye disease and diabetes and age-related macular degeneration. But most everyone is familiar with the bad effects of vessel destabilization. We think any disease where vessels leak and accumulate could benefit. How broad is this principle and how strong the application outside of the eye, we don't yet know."

Dr. Kang Zhang, associate professor of ophthalmology and visual sciences at the Moran Eye Center and an investigator with the U.'s Program in Human Molecular Biology and Genetics, touted the potential for developing drugs to activate Robo4. His lab worked with Li's, using the same eye disease animal models used for drug development, which could shorten the time it takes to get to human trials.

Like other treatments that affect an eye's blood vessels, this is injected, Li said.

He predicts an eventual "race to figure out how to make something smaller to activate this receptor so we can do it without injecting." Some treatments exist for AMD, the leading cause of blindness in people over 65, he said. For diabetic eye disease (the leading cause in younger adults), there are no proven therapies.

Li left the biotech field for academia five years ago specifically to research eye blood vessel instability and ways to reverse it. His U. collaborators on the study include graduate student Christopher A. Jones and Nyall London, an M.D./Ph.D. candidate in the Department of Oncological Sciences and the Program in Human Molecular Biology and Genetics, as well as several other researchers from Li's lab. Others contributed from the University of California, San Diego; the National Heart, Lung and Blood Institute; and Harvard Medical School. Much of the funding came from the National Heart, Lung and Blood Institute and the National Eye Institute.

E-mail: lois@desnews.com