Chicago,
IL (7/9/99)- The discovery of a protein in the human eye that inhibits
the growth of new blood vessels could lead to the development of drugs to
prevent common vision-stealing diseases, report researchers at. Northwestern
University.
Noel Bouck and colleagues at the Robert H. Lurie Cancer Center determined
that a protein called pigment epithelium-derived factor (PEDF) prevents blood
vessels from growing into the cornea and the vitreous, the parts of the eye
through which light passes. The researchers report that the amount of PEDF
produced by retinal cells correlates with oxygen concentrations. This suggests
that the loss of PEDF that occurs in some eye diseases could set the stage
for the formation of new vessels. Uncontrolled growth of new blood vessels
is a factor in diabetic retinopathy and macular degeneration, the leading
causes of blindness in the Western world.
Unchecked vascular proliferation is also a factor in the development of many
cancers, including a common cancer of the eye called retinoblastoma. Previous
research showed that PEDF promotes differentiation of the cells in retinoblastoma
tumors, causing them to resemble non-dividing neurons.
"PEDF may have a double-barreled effect against retinoblastomas -- first,
slowing their growth by binding to the endothelial cells that form new blood
vessels and preventing the angiogenesis that the tumor needs and, second,
binding directly to the tumor cells themselves, causing them to differentiate
and thus grow more slowly," Bouck said.
In laboratory studies, the researchers tested PEDF against a number of compounds
known to induce the formation of new vessels. They found PEDF to be one of
the most potent natural inhibitors of neovascularization ever seen. They are
hopeful that, given its high potency and the broad range of angiogenic inducers
against which it can act, PEDF may prove to be a useful treatment for neovascular
diseases such as diabetic retinopathy, and retinoblastoma, a difficult to
treat eye tumor.
"These results raise the possibility that returning PEDF to its normal
level in diabetic patients whose vision is deteriorating might prevent new
vessels from overgrowing and leaking and thereby slow the clouding of their
vision," the researchers note.
In a related study, researchers at the University of Texas report important
progress in the search for a treatment of age-related macular degeneration,
a leading cause of blindness. They found that inactivating a gene in mice
called ABCR gene interfered with the transport of an essential protein, Rim
protein (RmP) in the retina's photoreceptor cells. When a mutation occurs
in ABCR, then RmP dysfunctions and cannot perform its transporter role.
"Our research revealed, among other things, the biochemical change in patients
with Stargardt's disease that makes vision more difficult when coming from
sunshine into a dimly lit room," said Dr. Gabriel Travis, associate professor
of psychiatry and an investigator in the Center for Basic Neuroscience at
UT Southwestern. This symptom is called delayed dark adaptation, an early
sign of the illness, which is the most common form of juvenile macular degeneration.
Stargardt's disease affects about one in 20,000 children over age 6, and
age-related macular degeneration develops in approximately one in four adults
over 65. Both disorders affect central vision, essential for reading, driving
and face recognition.
The mice used in thsi study were genetically engineered to lack the ABCR
gene and the RmP protein associated with it. In normal mice, RmP inhibits
accumulation in the retinal pigment epithelium (RPE) of lipofuscin, a brown
pigment generally associated with aging. The buildup of lipofuscin poisons
the RPE, which then cannot perform its role of keeping photoreceptor cells
healthy. The unhealthy cells begin to die, resulting in vision loss. The lipofuscin
accumulation seen in the mice is identical to what is observed in humans with
Stargardt's and age-related macular degeneration.
"Although the mouse retina does not contain a macula, our studies offer
a possible explanation for vulnerability of the macula in several human blinding
diseases," Travis said. "We observed complete inhibition of lipofuscin accumulation
when mutant rodents were raised in total darkness. This observation suggests
that patients with Stargardt's disease and some forms of AMD could slow the
progression of their blindness by wearing sunglasses and avoiding bright light."
Both Stargardt's disease and macular degeneration are chronic, progressive
incurable diseases. The new research offers the hope of a new treatment strategy.
If researchers can determine a way to inhibit the accumulation of lipofuscin
in retinal pigment epithelial cells, these diseases might be curable.
Dr. Bouck's work appears in the July 9, 1999 issue of Science. Dr. Travis'
research appears in the July 9, 1999 issue of Cell.
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