"What we would like to do is to take a basic science laboratory observation as close to the clinic as we can," says Martin Friedlander, M.D., Ph.D., the principal investigator on the grant, an associate professor in TSRI's Department of Cell Biology and Chief of the Retina Service in the Division of Ophthalmology, Department of Surgery at Scripps Clinic.
The vast majority of diseases that cause catastrophic vision loss do so as a result of abnormal angiogenesis, the uncontrolled growth of new blood vessels in the back of the eye. The leading cause of vision loss in patients who are above the age of 65 is macular degeneration. Twelve to fifteen million people in this country alone have macular degeneration, and 10 to 15 percent of them will suffer acute loss of vision.
In patients under the age of 65, the leading cause of vision loss is due to a complication of diabetes known as diabetic retinopathy. Some 16 to 18 percent of the U.S. population has diabetes. Virtually every one of those patients will eventually have a form of diabetic retinopathy after 20 years and every year 40,000 of them lose vision as a result of complications from diabetes.
Both macular degeneration and diabetic retinopathy are characterized by abnormal angiogenesis. In the case of macular degeneration, new blood vessels grow under the retina. In diabetic retinopathy, abnormal vessels grow on top of the retina. The effect is much the same; the vessels interfere with normal structures or the transmission of light to the back of the eye, impeding vision.
There is currently no effective treatment for the vast majority of these patients, but for several years, researchers have sought compounds that could inhibit angiogenesis, prevent the growth of new blood vessels and reduce the vision loss associated with vascular proliferation, fluid leak and bleeding.
Currently, some of these anti-angiogenic compounds are in clinical trials, but there is no indication yet how successful these will be in treating neovascular eye diseases.
A new class of anti-angiogenic molecules was described last year by Friedlander and Paul Schimmel, Ph.D., who is Ernest and Jean Hahn Professor of Molecular Biology and Chemistry at TSRI and a member of the Skaggs Institute for Chemical Biology. In two papers published in the Proceedings of the National Academy of Sciences, the research groups of Friedlander and Schimmel, along with the group of TSRI Professor of Immunology David Cheresh, Ph.D., described the antiangiogenic activity of a fragment of the human protein tryptophanyl-tRNA synthetase (TrpRS)--an enzyme involved in the synthesis of proteins. The original work was done by Schimmel and his laboratory, who had been studying RNA synthetases for a number of years and discovered the anti-angiogenic effect of TrpRS a few years ago.
"People typically talk about 20, 30, 40 percent inhibition [of new vessel formation] for the compounds that are in clinical trials," says Friedlander. "What we have seen in our pre-clinical studies is that in 70 percent of cases, you get 100 percent inhibition. Our hope is that TrpRS may be something that will be useful in the treatment of neovascular eye disease."
Other investigators at TSRI who are involved in the recently funded work include: Dale L. Boger, Ph.D., Richard and Alice Cramer Professor of Chemistry; associate professor Glen Nemerow, Ph.D., of TSRI's Department of Immunology; and Gary Siuzdak, Ph.D., who is an adjunct associate professor in the Department of Molecular Biology.
The project, titled "Fragments of TrpRS to treat Neovascular Eye Disease," was funded by the National Eye Institute, which is one of the institutes within the National Institutes of Health.