Eye drops reduce signs of macular degeneration in mice

Cholesterol-lowering eye drops may one day help preserve sight in people with a common cause of age-related vision loss, a new study suggests.

In old mice, eye drops that stimulate cells to shed cholesterol rejuvenated immune cells to fight off blood vessels encroaching into the retina, a hallmark of advanced age-related macular degeneration. The finding suggests that cholesterol buildup in the eye helps promote the condition, a leading cause of vision loss in people 50 and older.

Macular degeneration comes in two forms, dry and wet. In the dry, early stage of the disease, cells in the center of the retina die, blurring vision. This stage is often characterized by yellow clumps of lipids, including cholesterol, in the retina. These deposits can be a warning sign that a person is at risk of developing the wet form of the disease, in which blood vessels invade the back of the eye and leak, killing retinal cells. Patients are left with a hole in the middle of their field of vision.

In previous research, Rajendra Apte of the Washington University School of Medicine in St. Louis and colleagues showed that immune cells called macrophages are involved in macular degeneration. His team found that macrophages protect vision by halting blood vessels creeping into the eye. But the researchers also discovered that aging macrophages become bloated with cholesterol and can’t stop blood vessel invasion.

For the new study, published April 2 in Cell Metabolism, Apte’s team collected macrophages from young and old mice and people. Then the researchers counted the number of proteins that pump cholesterol, called ABC transporters, on the cells. Old macrophages had fewer pumps than young cells did. The old cells, particularly those with lower numbers of a cholesterol pump called ABCA1, couldn’t combat blood vessel growth as well as the young ones could.

The team traced the diminished cholesterol-pumping ability to a small piece of genetic material called a microRNA. The microRNA miR-33 builds up as cells age, the researchers discovered. Because this piece of RNA puts the brakes on production of the ABCA1 pump, the result is that macrophages can’t jettison cholesterol the way they once did.

Blocking miR-33 or using drugs that stimulate other cholesterol-shedding mechanisms could restore macrophages’ ability to fend off blood vessel proliferation, Apte’s team found. Mice given injections of either the microRNA blocker or the drugs had fewer encroaching blood vessels in their eyes than placebo-treated animals did. And eye drops that stimulate cells in the eye to dump cholesterol  worked as well as the injections, the researchers found. That could mean that doctors could treat just people’s eyes, potentially avoiding side effects that might accompany whole-body therapies.

Apte’s group has shown that cholesterol is a player, particularly in the “wet” form of macular degeneration, says Anand Swaroop, a geneticist who studies eye diseases at the National Eye Institute in Bethesda, Md. But Swaroop doubts it is the underlying cause of the disease. Genetic studies indicate that how well cells dump cholesterol is just one of many factors that add up to produce macular degeneration, he says.

A treatment based on lowering cholesterol in the eye is still years and many tests of safety and efficacy away, Swaroop says, but adds that he’d be delighted if eye drops could stop the disease. Wet macular generation is often treated with monthly injections of drugs that inhibit blood vessel growth. “When you’re 80 years old,” he says “you don’t want to be pricked in the eye every month.”