Tests in a mouse model of macular degeneration have shown that anti-depressant drugs already on the market prevent damage to the light cells in the retina. In a study published in Proceedings of the National Academy of Sciences, a University of Wisconsin—Madison research team pinpoints how immune abnormalities beneath the retina result in macular degeneration. Team leader Aparna Lakkaraju, an assistant professor of ophthalmology and visual sciences, focused on two protective mechanisms that are compromised during the gradual onset of the disease.
Lakkaraju explains that macular degeneration starts with injury to the retinal pigment epithelium (RPE), a single layer of cells beneath the rods and cones at the back of the eye. She and her colleagues focused on two protective mechanisms: the protein CD59, which regulates complement activity when attached to the outside of RPE cells; and lysosomes, spherical structures that plug pores created by the complement attack.
“CD59 prevents the final step of attack that forms the pore,” Lakkaraju says, but if the complement attack is not defeated, the opening in the RPE cell membrane allows the entry of calcium ions, which spark a long-term, low-grade inflammation that inhibits both protective mechanisms, creating a vicious cycle of destruction.
The study identified an enzyme called aSMase, which is activated by excess cholesterol in the RPE and is toxic to the retina. Drugs used to treat depression neutralized that enzyme and restored the protection and the health of RPE cells in the mouse model.
Several FDA-approved drugs that inhibit aSMase are already on the market for treating depression. In this study, the antidepressant desipramine, administered to mice in their drinking water, restored CD59, preventing deterioration of the retina.
A patent application for the idea of preventing macular degeneration by blocking aSMase has been filed by the Wisconsin Alumni Research Foundation. “We hope a pharmaceutical company will license this process and start the necessary preclinical and clinical trials,” Lakkaraju says. “The epidemiological data are there, and now we have fairly convincing mouse data. The safety profiles of these drugs have been documented for decades. There is certainly no guarantee of success, but we need a way to prevent macular degeneration. I am realistic, but hopeful, that better knowledge of this disease process could be the key.”
The research was funded by the National Institutes of Health, Research to Prevent Blindness, Retina Research Foundation and other sources.