Discovery Could Lead to New Treatments for Diabetes-Related Vision Loss and Blindness

February 2007 - The Juvenile Diabetes Research Foundation, the world's leading charitable funder of type 1 diabetes research, announced today that JDRF-funded researchers have identified a group of proteins that may play critical roles in causing blood vessel leakage in the eyes of people with two forms of diabetic retinopathy.

These findings result from years of research conducted by Edward Feener, Ph.D., and his team of investigators at the Joslin Diabetes Center in Boston, and are published in the Jan. 28, 2007, online edition of the journal Nature Medicine.

Over the years, Dr. Feener and his team have compiled the most complete inventory of proteins present in the vitreous - the gel that fills the cavity between the lens and the retina. They also discovered that one of these molecules causes the leakage of retinal blood vessels, which contributes to the retinal swelling (or diabetic macular edema) often associated with advanced diabetic retinopathy. Their findings suggest potential new therapeutic targets for the treatment of proliferative diabetic retinopathy and macular edema, and could provide new opportunities for treating cerebral swelling caused by head injury, stroke and other conditions.

"Millions of people worldwide live with diabetic retinopathy and the accompanying threat of severe vision loss or blindness. While some treatment is available in the late stages of this condition, the incidence of proliferative diabetic retinopathy and diabetic macular edema still pose the serious threat of sight loss. Dr. Feener's findings could provide new opportunities for the development of treatments for diabetes-related vision loss," said Dr. Helen Nickerson, Scientific Program Manager for Complications at JDRF.

Diabetic retinopathy is one of the most common complications of diabetes and is characterized by a range of abnormalities that develop from damage caused by high blood glucose levels. Proliferative diabetic retinopathy is diagnosed when the retina begins to form new blood vessels to counteract this damage, which in turn often bleed and blur or block vision. More than 700,000 patients in the United States have proliferative diabetic retinopathy, and more than 63,000 patients develop it annually. Diabetic macular edema occurs as the leaky blood vessels cause the central area in the retina responsible for sharp central vision (the macula) to swell. It affects more than 500,000 patients in the U.S., with 56,000 new cases diagnosed yearly.

Researchers have had difficulties studying these diseases because rodents with diabetes, which investigators often use to study diabetic eye disease, do not naturally produce many of the changes in the retina observed in humans. Dr. Feener and his colleagues developed a revolutionary high-speed protein analysis technology to identify protein abnormalities in people with and without diabetic eye disease. Working with a network of collaborators at Joslins Beetham Eye Institute and the Santa Barbara Cottage Hospital Eye Center in California, they obtained samples from 25 people undergoing surgery for a variety of conditions: eight of the patients did not have diabetes and therefore no diabetic eye disease; four had diabetes, but no diabetic retinopathy; and 13 had diabetic retinopathy. They identified 117 proteins (earlier attempts to catalog vitreous proteins had succeeded in identifying only 20 to 50) and detected 31 proteins that were present in the vitreous of patients with diabetes.

"By analyzing the protein composition in the human vitreous, we have identified a new group of molecules that may improve our understanding of the disease processes that contribute to diabetic retinopathy. By studying the actions of these proteins in both the retina and the brain, we have shown that our findings may have broad relevance for neurovascular leakage and swelling," says Dr. Feener, Investigator in Joslins Section on Vascular Cell Biology, Director of Joslins Proteomics Core, which hosted the study, and Assistant Professor of Medicine at Harvard Medical School.

One of the proteins was carbonic anhydrase 1, or CA-1, an enzyme that is normally found in red blood cells. "We suspected that high levels of this protein in the vitreous fluid might cause problems," says Dr. Feener. "When we tested it in the vitreous of rodents, we found a marked increase in blood vessel leakage, which is a fundamental process in diabetic retinopathy."

Performing additional studies with CA-1, the researchers showed that their findings have even broader relevance. "The eye is a neurovascular tissue with certain features similar to those of brain, and it is well known that hemorrhage in the brain, either from a hemorrhagic stroke or any cerebral bleeding, causes swelling," says Dr. Feener. "When we introduced CA-1 into the cerebral spinal fluid around the brain of rodent animal models we found that it also increased the swelling and the leakage of blood vessels in the brain." This discovery, he explains, could provide new opportunities for treating the cerebral swelling caused by head injury, stroke and other conditions.

Study participants included lead author, Ben-Bo Gao, Ph.D., of Joslin; additional collaborators from Section on Eye Research and the Beetham Eye Institute at Joslin included Lloyd Paul Aiello, M.D., Ph.D., Allen Clermont, M.S., Sven-Erik Bursell, Ph.D., Susan Rook, Stephanie Fonda, Ph.D., Paul G. Arrigg, M.D.; Vivek Srinivasan, M.S., Maciej Wojtkowski, Ph.D., and James Fujimoto, Ph.D., of the Massachusetts Institute of Technology; and Robert Avery, M.D., of the Santa Barbara Cottage Hospital Eye Center.

Source: Juvenile Diabetes Research Foundation International