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June 7, 1999

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Drug Stops Blinding Blood Vessel Growth in Mice

--Prevents Damage from Diabetic Retinopathy, Macular Degeneration

Scientists at Johns Hopkins and Novartis Ltd. Pharmaceuticals, in partnership with Novartis' CIBA Vision eye care unit, have identified a drug that completely stops the growth of abnormal blood vessels on or beneath the retinas of laboratory mice.

Results of the mouse studies, published in the June issue of the American Journal of Pathology, could mean that people at risk for blindness associated with macular degeneration or diabetes may one day be able to pop a pill to prevent blinding blood vessel growth. Vessels that grow abnormally in the eyes can leak fluid or blood, causing rapid and severe vision loss. Such growth is the hallmark of diabetic retinopathy and age-related macular degeneration, the leading causes of blindness in young and old people, respectively, in developed countries.

Human trials of the drug, called PKC 412, could begin early next year, says Peter A. Campochiaro, M.D., senior author of the study and a professor of ophthalmology and neuroscience at Hopkins.

"This is the first drug I've seen that has a knock-your-socks-off kind of effect," Campochiaro says. "Previous drug studies have only halted growth of abnormal vessels by roughly 50 percent, but this medication appears to stop it completely in three mouse models. Remarkably, the drug can be given orally, the preferred method of drug delivery in people. If these animal models are predictive, the drug should work in people."

In diabetics, high blood sugar through a cascade of events can lead to damage to normal retinal blood vessels and a decrease in the supply of oxygen and nutrients. The retina calls for back up by releasing vascular endothelial growth factor (VEGF), a substance that stimulates new blood vessels to grow to try to compensate. However, the back-up blood vessels generally are faulty; they leak, bleed and encourage scar tissue that detaches the retina, resulting in severe loss of vision. In macular degeneration, abnormal blood vessels grow beneath the central part of the retina, called the macula. They also leak, bleed and cause scarring that results in loss of central vision and with it, the ability to read or drive.

VEGF trips a switch that ignites a chain reaction culminating in new blood vessel growth. The switch is the VEGF receptor, a protein that is activated by VEGF after which it activates the next link in the chain. A few links downstream is protein kinase C, an enzyme that appears to be important in keeping the chain reaction going. Platelet-derived growth factor (PDGF) is structurally similar to VEGF and may stoke the fires of the chain reaction from another direction.

PKC 412 may mount a three-pronged attack on the chain reaction. It blocks the actions of the receptors for VEGF and PDGF, and also blocks protein kinase C. Campochiaro and his colleagues are trying to determine if one, two or all three of these actions are responsible for the dramatic effects of PKC 412. While PKC 412 blocks new abnormal blood vessel growth, it has no apparent adverse effects on normal, fully mature blood vessels.

Current treatments for diabetic retinopathy and age-related macular degeneration include laser treatment or surgery to eliminate the abnormal blood vessels. But, in addition to risks associated with surgery, the treatments do nothing to treat the underlying stimuli for blood vessel growth, Campochiaro says.

"As a result, the blood vessels tend to come back," he says. "Even with initially successful treatments, many patients still end up with severe loss of vision."

The study was supported in part by the U.S. Public Health Service; the National Eye Institute; Research to Prevent Blindness Inc.; the Juvenile Diabetes Foundation; CIBA Vision Inc.; Project Insight; the Association for Retinopathy of Prematurity and Related Diseases; and by private donors.

The study's other authors were Man Seong So, Nohoon Kwak, Hiroaki Ozaki, Haruhiko Yamada, Naoyuke Okamoto and Eri Yamada of Hopkins; and Doriano Fabbro, Francesco Hofmann and Jeanette M. Wood of Novartis.

Campochiaro is a consultant to CIBA Vision Corp. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Related Web sites:

Wilmer Eye Institute at Johns Hopkins-- http://www.wilmer.jhu.edu/
Dr. Campochiaro's laboratory-- http://www.wilmer.jhu.edu/Campo/index.htm
Novartis Pharmaceuticals-- http://www.novartis.com/
CIBA Vision-- http://www.cibavision.com/
National Eye Institute-- http://www.nei.nih.gov/
American Academy of Ophthalmology public information--http://www.aao.org/public/pi/


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