Macular Degeneration, Other Blood Vessel Diseases May be Treatable with Pills

Macular Degeneration, Other Blood Vessel Diseases May be Treatable with Pills

Oct 25, 2009 12:00 PM

SALT LAKE CITY—An international research group led by a University of Utah cardiologist has shown that people with diseases caused by leaky blood vessels, such as age-related macular (AMD) degeneration and diabetic retinopathy, might one day be able to take a pill to treat those devastating conditions.
In a study published Sunday in Nature Cell Biology online, Dean Y. Li, M.D., Ph.D., professor of internal medicine and director of the Molecular Medicine Program at the U of U School of Medicine, and colleagues identify a potential “small molecule” or pharmaceutical drug that stabilizes weak blood vessels and prevents them from leaking. Leaky blood vessels are a primary cause of AMD and diabetic retinopathy, two of the leading causes of blindness, and other diseases. The molecule, SecinH3, works by fooling cells into sensing that a receptor has been activated, triggering a process in which vessels are made stronger and less affected by inflammation.
“By fooling the cell, we’ve prevented inflammation from damaging blood vessels of the eye,” said Li, who’s also an investigator with the U of U’s Program in Human Genetics and Molecular Biology. “Our study is the proof of concept that this molecular pathway can be manipulated by a drug.”
Study co-author, Kang Zhang, M.D., Ph.D., director of the Institute for Genomic Medicine and professor of ophthalmology and human genetics at the medical school at the University of California, San Diego (UCSD), said the finding represents an important step in eventually treating diseases such as AMD and diabetic retinopathy. “This is a therapeutic advance for these prevalent blinding conditions, which affect millions of Americans that can lead to new treatments in the future.”
The study, conducted with colleagues at the University of Bonn, Germany, as well as UCSD, builds on groundbreaking research led by Li last spring. That study showed that when a cellular receptor called Robo4 was activated, blood vessels became stronger and stopped leaking in mouse models with AMD and diabetic retinopathy. The researchers identified a protein, called a ligand, that activates Robo4. These ligands are “large proteins,” which are often hard to turn into medicines for people.
Although their study showed that a ligand could stabilize blood vessels and treat AMD and diabetic retinopathy in mice, Li and his colleagues didn’t fully understand the process through which that happened. That led to the latest study to find out how Robo4 was involved in stabilizing blood vessels.
Using mice models and human cells, the investigation showed that when activated, Robo4 triggers a molecular process or “cascade” through which blood vessels are strengthened, which stops them from leaking fluid in response to inflammation. The cascade triggered by Robo4 occurs in a series of steps, according to Li. “The first step is when Robo4 is activated,” he said. “After that, there are a series of sequential steps by which the Robo4 receptor instructs blood vessels to strengthen.”

SecinH3 does not activate Robo4. It works by fooling the molecular pathway into falsely sensing that the receptor has been activated. When that happens, the cascade is put into motion, just as if Robo4 has been activated, but bypasses the first step.
Although their study showed SecinH3 does activate the molecular cascade that stabilizes blood vessels, Li said it is unlikely that this particular molecule would ultimately be the basis of drug to treat diseases caused by weak and leaking blood vessels. Unknown side-effects or other issues often preclude the first molecules identified as potential drugs from actually going to market. But now that their research has shown that a small molecule drug can help stabilize blood vessels, the search for a usable compound can begin, according to Li.
That search will take years, however, before a drug can come to market, and will have to be undertaken by private industry. The resources and money required to develop a drug that receives U.S. Food and Drug Administration approval are well beyond that of an academic laboratory, Li said. “We’ve taken it as far as we can.”

Funding for the study was provided in part by the American Heart Association, Juvenile Diabetes Research Foundation, National Institutes of Health, and the Burroughs Wellcome Fund.

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