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Senior Citizen Health & Medicine
Robo4 Stops Age-Related Macular Degeneration,
Diabetic Retinopathy in Mice
‘This is a major breakthrough in an area where the
advances have been minimal’
 March 17, 2008 - Two major eye diseases and leading
causes of blindness - age-related macular degeneration and diabetic
retinopathy - can be reversed or even prevented by drugs that activate a
protein found in blood vessel cells, researchers at the University of
Utah School of Medicine and several other institutions have announced in
a new study.
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Damage from both diseases was prevented and even
reversed when the protein, Robo4, was activated in mice models that
simulate age-related macular degeneration (AMD) and diabetic
retinopathy, according to Dean Y. Li, M.D., Ph.D., senior author of the
study published March 16 in Nature Medicine online.
Robo4 treated and prevented the diseases by
inhibiting abnormal blood vessel growth and by stabilizing blood vessels
to prevent leakage. Abnormal blood vessel growth and leakage are two
primary factors in both age-related macular degeneration (AMD) and
diabetic retinopathy.
But the study’s ramifications go beyond eye
diseases.
Serious infections such as SARS (Severe Acute
Respiratory Syndrome), for example, kill people when an infection
destabilizes blood vessels, allowing fluids to leak into the lungs.
Tumors hijack blood vessel growth to feed on nutrients and grow.
Although this study did not prove Robo4 would treat those diseases, Li
believes it merits investigation.
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Age-related macular degeneration is the most common
cause of legal blindness in senior citizens - people age 65 or older - and is expected to
become an increasingly common and costly health issue as the number of
older people in US increases.
Diabetic retinopathy is the
most common cause of legal blindness in working-age Americans.
Currently, there are an estimated 21 million people with diabetes. |
“Many diseases are caused by injury or inflammation
destabilizing blood vessels and causing them to leak fluid into adjacent
tissues as well,” said Li, professor of internal medicine and an
investigator with the University’s Program in Human Molecular Biology
and Genetics. “We found a natural pathway – the Robo4 pathway – that
counterattacks this by stabilizing blood vessels.”
“This discovery has significant implications for
developing drugs that activate Robo4 to treat AMD and diabetic
retinopathy,” said Kang Zhang, M.D., Ph.D., associate professor of
ophthalmology and visual sciences at the University of Utah’s John A.
Moran Eye Center and an investigator with the University’s Program in
Human Molecular Biology and Genetics.
Li and Zhang’s laboratories closely collaborated on
the research, using the same animal models of AMD and diabetic
retinopathy that are required for drug development. The collaboration
means the time required to test the approach in people could be
shortened, perhaps by years. Nonetheless, both Zhang and Li caution that
getting new drugs to market still would take a number of years.
Randall J. Olson, M.D., director of the
University’s John A. Moran Eye Center and professor and chair of
ophthalmology and visual sciences, called Li’s finding historic.
“This is a major breakthrough in an area where the
advances have been minimal,” Olson said. “We are excited about taking
this opening and moving the frontier forward with real hope for patients
who have but few, often disappointing, options.”
The discovery is a prime example of basic science
research yielding a discovery with direct clinical applications,
according to Hemin Chin, Ph.D., director of ocular genetics program at
the National Eye Institute.
 “Given that vascular eye diseases, such as age
related macular degeneration and diabetic retinopathy, are the number
one cause of vision loss in the United States, the identification of new
signaling pathways that prevent abnormal vessel growth and leakage in
the eye represents a major scientific advancement,” said Chin.
Blood vessel growth (angiogenesis) is critical in
human development and as a response to injury or disease. In earlier
research, Li had shown that a family of proteins, netrins, induce blood
vessel and nerve growth in mice, a discovery with important
ramifications for potential therapies to help people with too few blood
vessels.
But when the body grows new blood vessels at the
wrong time or place, these blood vessels are often unstable and weak,
which causes them to leak and potentially lead to diseases such as
macular degeneration and diabetic retinopathy.
In 2003, Li’s laboratory cloned Robo4 and showed it
served the opposite function of netrins by inhibiting blood vessel
growth and the destabilization that causes leakage. Robo4 is found only
in cells in the interior surface of blood vessels and is activated by a
protein called Slit. After being activated, Robo4 initiates a chain of
biochemical events to stabilize blood vessels and prevent uncontrolled
growth.
“Everything in biology has a yin (negative) and a
yang (positive), and in the previous paper on netrins we brought
attention to a new signaling pathway that induces vessels and nerves to
grow,” Li said. “Robo4 is the yin to that process, preventing new vessel
growth by stabilizing the integrity of mature blood vessels.”
Editor’s Notes:
Li’s collaborators on the study from the University
of Utah include co-first authors 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. Several other researchers from Li’s lab also contributed to
the project. In addition, researchers from the University of California,
San Diego, the National Heart, Lung, and Blood Institute, and Harvard
Medical School were part of the study.
The study was funded largely by the National Heart,
Lung, and Blood Institute and the National Eye Institute, both are part
of the National Institutes of Health.
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