Article Describes New Marker of Key Retinal Cells, Therapy to Slow Abnormal Vessel Growth
Los Angeles - May 19, 2006 - As a result of recent research described in the May 2006 issue of the American Journal of Pathology, changes in specialized cells involved in proliferative diabetic retinopathy and similar disorders may be diagnosed more reliably than before and the effectiveness of existing treatments may be significantly improved through a new combination approach found effective in an animal study.
The multi-center studies, led by scientists at Cedars-Sinai Medical Center’s Ophthalmology Research Laboratories, provide new details of the effects of a key cellular enzyme, protein kinase CK2, on specific cells (astrocytes) that guide the formation of blood vessels in the retina. In normal “angiogenesis”– the process leading to the formation of new vessels – equilibrium exists between hormones and chemicals that promote growth and those that inhibit growth. But in proliferative disorders, such as diabetic retinopathy, this balance is lost and the development of new vessels continues unchecked.
The most severe eye-related complication of diabetes and a major cause of blindness among working-age people worldwide, diabetic retinopathy is a complex process, resulting from a variety of biochemical actions that lead to oxygen deprivation (hypoxia) of the retina. As the disease progresses, the small blood vessels, or capillaries, of the retina close, and astrocytes and other cells trigger the release of natural body chemicals to begin the creation of new vessels.
Although CK2 exists in all body cells, the researchers found that immunohistochemistry testing could detect it at the protein level in only one type of cell in the retina: the astrocytes. CK2 is found in normal retinas, those with diabetic retinopathy and those undergoing neovascularization after hypoxia. Therefore, examining the level of activity (expression) of CK2 may provide a unique and accurate method to evaluate the retina’s status.
In fact, in animal studies, CK2 expression was elevated in astrocytes associated with superficial retinal blood vessels during intraretinal neovascularization. Furthermore, the addition of CK2 inhibitors blocked the formation of new vessels and decreased CK2 expression in the astrocytes.
“Previous data from our laboratory established the importance of CK2 for retinal neovascularization. Now we present evidence that CK2 may be considered a new immunohistochemical marker for retinal astrocytes that is more reliable than any now existing,” said Andrei A. Kramerov, MD, PhD, research scientist and the first author of the article.
In addition, the researchers found for the first time in an animal study that antiangiogenic combination therapy to reduce retinal neovascularization – administering CK2 inhibitors with a hormone (somatostatin) therapy – provides significantly better results than either treatment alone.
“Many anti-angiogenic compounds are being tested in animal models and in human clinical trials in an attempt to prevent the progression of diabetic retinopathy. Most of these therapies are given one at a time, with only limited effectiveness,” said Alexander V. Ljubimov, PhD, director of the Ophthalmology Research Laboratories at Cedars-Sinai and senior author of the journal article. “In collaboration with Maria Grant’s group, we found that when a CK2 inhibitor was combined with the somatostatin analog (synthetic hormone) octreotide, we were able to achieve the same magnitude of effect as with a five-fold higher dose of somatostatin alone. If additional studies support our findings, combination therapy may be more potent and allow the dose to be reduced in diabetic patients.”
This view is shared by the main collaborator of Cedars-Sinai group, Maria B. Grant, M.D., from the University of Florida at Gainesville.
Findings reported in the American Journal of Pathology article resulted from several animal studies and postmortem studies of human eyes, and the research team included scientists from the University of Florida, the Minneapolis Veterans Affairs Medical Center, Vanderbilt University, the University of Southern California, and the Universtat des Saarlandes in Homburg, Germany. Funding was provided by the Skirball Program in Molecular Ophthalmology, Cedars-Sinai’s Department of Surgery, and a grant from the National Institutes of Health.
Citation: American Journal of Pathology, May 2006, “Expression of Protein Kinase CK2 in Astroglial Cells of Normal and Neovascularized Retina.”