Story guest authored by Derek Waldner with contributions by Dr. Mary Sunderland. Derek is a neuroscience graduate student at the University of Calgary and a knowledge translation intern at the FFB.
Even though age-related macular degeneration (AMD) is the leading cause of blindness in people over the age of 50, we still don’t understand the cause of the disease. Thanks to Foundation-funded research, our understanding just took a giant leap forward! Groundbreaking research by Dr. Jean-Sébastien Joyal and collaborators across twelve institutions uncovered significant insights that pave the road to future therapies.
The vision loss that happens in AMD is caused by the abnormal growth of leaky blood vessels in the eye’s retina. It’s widely believed that this abnormal growth is triggered by oxygen deprivation. Amazingly, the research team discovered another cause: energy-starved photoreceptors.
“The inability of photoreceptors – nerve cells that capture light and generate vision – to produce energy may drive abnormal blood vessels to invade the retina” said Dr. Joyal, an intensive care pediatrician at CHU Sainte-Justine and professor in the Department of Pediatrics at the University of Montreal. “We also discovered that photoreceptors do not rely exclusively on glucose to produce energy as previously thought, but also use lipids as a fuel substrate (like the heart, for example)” he said. These findings change the way we understand the cause of AMD, which opens the door to new treatments.
As individuals age, the function of some cellular processes – including processes associated with energy metabolism – is known to decline. In addition, photoreceptors consume a surprising amount of fuel. “They have the highest concentration of mitochondria — the “furnace” of the cell — and use more energy than any other cell in the body,” explained Dr. Lois Smith, who collaborated with Dr. Joyal on the study. Dr. Smith described how photoreceptors “have to be ‘on call’ all the time to signal light perception.” Because of this, photoreceptors have evolved a special system to ensure they get enough fuel. The research team demonstrated, for the first time, that photoreceptors need lipids, or fats to function, and that they have special receptors and a special lipid sensor (FFAR1).
When the researcher team tricked photoreceptors into nutrient scarcity (by manipulating FFAR1), they discovered that more vascular endothelial growth factor (VEGF) was released. Increased VEGF leads to abnormal blood vessel growth, which causes vision loss in AMD. VEGF blockers already exist to treat AMD (such as Lucentis, Eylea and Avastin). The team’s important discovery enables the development of new drugs to act on FFAR1 before (or “upstream”) of VEGF. The hope is that this would result in an even more effective treatment for AMD. The team’s next steps will be to check if people have lipid sensors similar to the ones that were identified in the animal model. If so, existing inhibitors could be tried in clinical trials. FFAR inhibitors are already in clinical trials for diabetes.
We are proud that this FFB-funded discovery changes the way we think about the eye’s biology. This is why the research was published in the very prestigious journal Nature Medicine: the entire biomedical community needs to know about it! (It also happens to be Dr. Joyal’s second publication there in two years.) Thank you to all of the FFB donors for supporting Dr. Joyal as his team continues to expand our knowledge and open avenues to new sight-saving treatments.
About the Study:
The article “Retinal lipid and glucose metabolism dictates angiogenesis through lipid sensor Ffar1” was published in the journal Nature Medicine on March 14, 2016. Jean-Sébastien Joyal, MD, PhD is an intensive care pediatrician at CHU Sainte-Justine, researcher at the CHU Sainte-Justine Research Center, and professor in the Department of Pediatrics at the University of Montreal. He is first author of the study. His work was supported by the Burroughs Wellcome Fund Career Award for Medical Scientists; Foundation Fighting Blindness; Canadian Institute of Health Research (CIHR); Fonds de Recherche du Québec — Santé (FRQS); Canadian Child Health Clinician Scientist Program; and CIHR New Investigator Award.
Co-Authors: Sun Y, Gantner ML, Shao Z, Evans L, Saba N, Fredrick T, Burnim S, Kim JS, Patel G, Juan AM, Hurst CG, Hatton CJ, Cui Z, Pierce KA, Bherer P, Aguilar E, Powner MB, Vevis K, Boisvert M, Fu Z, Levy E, Fruttiger M, Packard A, Rezende FA, Maranda B, Sapieha P*, Chen J, Friedlander M, Clish C and Smith L