What Triggers Mutant ELOVL4 Induced Blindness in STGD3?

Both Age-Related Macular Degeneration (AMD) and juvenile autosomal dominant Stargardt macular dystrophy (STGD3) share similar clinical features that result in irreversible blindness. The only difference is that, while AMD blindness starts in people over 60 years of age, STGD3 blindness starts in their teenage years. Dr. Agbaga and his team reasoned that since AMD and STGD3 share similar clinical features, there must be a common mechanism that contributes to the death of photoreceptor cells leading to blindness in both types of patients and that identification of this mechanism will help us to develop better drugs for treating these patients. The long-term goal of Dr. Agbaga’s studies is to use animal models of STGD3 to hunt and identify what sets off the death of the photoreceptor cells in these patients, with the goal that once they find the culprit, they can design effective drugs to silence it and preserve vision in STGD3 and some AMD patients.

Dr. Agbaga has a long-term research interest in combining advances in molecular biology, lipidomics, proteomics, and biochemical assays to dissect the mechanism underlying blinding eye diseases. In particular, his goal is to discover, develop, and evaluate possible future treatments for macular degenerative diseases such as STGD3 and AMD, both of which have no known cures. Currently, Dr. Agbaga’s team is working on understanding what causes macular degeneration in teenagers with inherited mutations in a gene called Elongation of Very Long Chain Fatty Acids-4 (ELOVL4). Inheritance of a single copy of the mutant ELOVL4 gene is sufficient to induce blindness in STGD3 patients in their teenage years. The team was the first to show that the normal ELOVL4 protein makes the unique combination of omega-3 and omega-6 fatty acids that are found in the retina. The presence of the mutant ELOVL4 decreases the amount of these fatty acids in the retina. At the same time, the mutant ELOLV4 protein seems to have a negative influence on the normal ELOVL4 protein, causing it to be misrouted to the wrong cellular compartments in photoreceptor cells. Thus, it is not clear whether the mutant ELOVL4 induces macular degeneration through dominant negative (loss-of-function) or toxic gain-of-function mechanisms – either is possible.

With the grant from the BrightFocus Foundation, the team will focus on the identification of proteins that interact in vivo with the mutant ELOVL4 to exert a dominant negative effect on the normal ELOVL4, and how misrouting of the mutant ELOVL4 to photoreceptor outer segments (the part of the cell that absorbs light) leads to early onset retinal cell death in STGD3 patients. The team will achieve these goals by using novel molecular and biochemical approaches that they and others have developed. Successful completion of the experiments will help to better understand the mechanisms that induce macular degeneration in STGD3. They hope to develop experimental therapeutic approaches to inhibit the dominant negative influence of the mutant ELOVL4 protein on the normal ELOVL4 protein by using chemical and molecular inhibitors on animal models of human disease. If they successfully rescue photoreceptor degeneration in these STGD3 models with their novel approach, they could progress into human clinical trials for treating STGD3 patients. Since macular dystrophy in STGD3 shares similar pathological features with dry AMD, understanding the mechanism that signals cell death in STGD3 animal models will help with the design of effective therapeutic strategies for both STGD3 and some forms of dry AMD.