New insights could potentially change the treatment of two diseases causing blindness: “Wet” age-related macular degeneration (AMD), the leading cause of severe vision loss in Americans over 60, and a less common condition called macular telangiectasia (MacTel) that occurs in middle age.
Both diseases are caused by abnormal growth of misshapen, leaky blood vessels in the eye that damages the macula, the central part of the retina needed to for straight-ahead vision.
The trigger for this pathologic process had been widely thought to be oxygen deprivation. However, findings published today by Nature Medicine suggest another cause: dysfunctional energy metabolism in the eye that starves the retina’s photoreceptors of fuel.
Senior investigator Lois Smith, MD, PhD, an ophthalmology researcher at Boston Children’s Hospital believes it may be possible to treat AMD and MacTel with drugs that help starving photoreceptors take in nutrients.
Meeting the eye’s high energy demand
Light-capturing 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,” Smith says. “They have to be ‘on call’ all the time to signal light perception and have to recycle their components constantly.”
Because of this, photoreceptor cells have evolved a special system to ensure they get enough fuel: While they were previously assumed to be powered by glucose, Smith’s team showed that photoreceptors also need lipids, or fats. In fact, they have special receptors to take up fatty acids, plus a special lipid sensor, FFAR1, that curtails glucose uptake when fatty acids are available.
Smith’s team, including Jean-Sébastien Joyal, MD, PhD, and Ye Sun, PhD, manipulated the fatty acid receptors in mice, leaving photoreceptors unable to take in lipids, which continued to circulate in the blood. This, the researchers showed, had the effect of leaving photoreceptors unable to get glucose either — resulting in energy starvation.
“When blood lipids are elevated, the lipid sensor says, ‘we don’t need glucose, we have enough lipids here,’ and it shuts off glucose uptake inappropriately,” Smith explains.
The energy-starved photoreceptors sent out a cry for help, calling for new blood vessels to bring them nutrients, the team found. They did this by secreting large amounts of vascular endothelial growth factor (VEGF), a signaling protein well known to encourage abnormal blood-vessel growth in macular disease.
A new drug therapy for macular disease?
While VEGF blockers such as Lucentis are already being used in AMD, they have systemic side effects, blocking even healthy, necessary growth of blood vessels. “It could be more effective and safer to go upstream of VEGF and solve the energy problem early,” Smith says.
It may be possible to do that by blocking the lipid sensor, FFAR. The team tried it and found that photoreceptor cells were able to keep taking in glucose and, as a result, the mice had far fewer diseased vessels.
Another potential target is the transporter that brings glucose into cells, but it is harder to reach with drugs, whereas drugs targeting FFAR are already in clinical trials for diabetes.
Smith believes that energy starvation contributes to age-related macular disease in two ways: not only through the actual lack of fuel, but also because mitochondria become less efficient at using energy as people age. Abnormal lipid metabolism and mitochondrial dysfunction are both associated with aging and both are important risk factors for AMD, Smith notes.
The team’s next steps will be to see if people have lipid sensors similar to those in mice. If so, existing inhibitors could be tried in clinical trials in an effort to increase glucose uptake, Smith says. So could dietary interventions using different types of lipids.
“There are no good model systems for AMD, so it’s hard to get at the human disease,” Smith says. “The lipid receptor gives us a way to look at humans and see how they function.”
The study’s supporters include the National Eye Institute (EY024868, EY017017, EY022275), the Lowy Medical Research Institute, the European Commission, the Burroughs Wellcome Fund Career Award for Medical Scientists, Foundation Fighting Blindness of the Canadian Institute of Health Research 143077, the Knights Templar Eye Foundation, the Bernadotte Foundation, Boston Children’s Hospital Ophthalmology Foundation, the Bright Focus Foundation and Mass Lions Eye Research Inc.