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
"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.