Macular degeneration insight identifies promising drugs to prevent vision loss

July 18, 2016 by David Tenenbaum, University of Wisconsin-Madison

In a study published this week in the 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, a common condition that often causes blindness.

Aparna Lakkaraju, an assistant professor of ophthalmology and visual sciences, focused on two protective mechanisms that are compromised during the gradual onset of , which degrades and can destroy the central vision needed to read and recognize faces.

In tests in a mouse model of macular degeneration, drugs that are already on the market prevented damage to the cells that sustain the light-sensitive cells in the eyes.

"These studies raise the possibility of treatments that could slow or prevent macular degeneration," says Lakkaraju.

Macular degeneration destroys in about 2 million Americans, mainly among the elderly, and is largely untreatable.

Although macular degeneration eventually damages or kills the light-sensitive rods and cones, Lakkaraju explains that it starts with injury to the retinal pigment epithelium (RPE). The RPE, a single layer of cells beneath the rods and cones at the back of the eye, performs many functions essential for healthy vision. The damage starts with a disturbance of immune proteins called complement, which normally kill disease-causing organisms by boring holes in their cell membranes.

"The light-detecting cells in the retina are totally dependent on the RPE for survival," says Lakkaraju, "but the RPE cells are not replaced through the lifespan. So we asked, 'What are the innate protective mechanisms that keep the RPE healthy, and how do they go awry in macular degeneration?'"

In a study performed with colleagues Li Xuan Tan and Kimberly Toops, Lakkaraju 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 (a function that Lakkaraju's team first detected in the RPE).

Together, they offer an in-depth defense, Lakkaraju says.

"CD59 prevents the final step of attack that forms the pore," Lakkaraju says. "Once a pore forms, the cell can move a lysosome to close it."

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 inflammation in the RPE damages mitochondria, structures that process energy inside all cells. This could eventually lead to a decline or death of the photoreceptor cells, once they are deprived of their essential housekeepers. The result is the loss of central, high-resolution vision.

Lakkaraju pursued her research in RPE cells isolated from pig eyes, and in mice that lack a protein—a deficiency that causes an inherited form of macular degeneration called Stargardt disease.

Crucially, her study identified an enzyme that is activated by excess cholesterol in the RPE, which neutralizes both protective mechanisms, and found that drugs used to treat depression neutralized that enzyme and restored the protection—and the health of RPE —in the .

Epidemiological studies by Ronald and Barbara Klein, also at the UW-Madison Department of Ophthalmology and Visual Sciences in the UW School of Medicine and Public Health, have linked long-term use of some of the same drugs with a decreased susceptibility to macular degeneration.

The drugs that helped restore protections in the RPE were chosen for their ability to remove excess cholesterol or inhibit aSMase, an enzyme involved in the toxic process, Lakkaraju says.

"There are several FDA-approved drugs that inhibit aSMase. We found that the antidepressant desipramine, administered to mice in their drinking water, restored CD59 on the cell surface, decreased reactive oxygen species, and prevented mitochondrial fragmentation.

"My lab is interested in the earliest stages of macular degeneration, because we cannot reverse the loss of RPE and photoreceptors," Lakkaraju says. A patent application for the idea of preventing macular degeneration by blocking aSMase has been filed by the Wisconsin Alumni Research Foundation.

Given the likely increase in macular degeneration among an aging population, and the current lack of alternatives, "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."

Explore further: Study reveals mechanisms of dry age-related macular degeneration

More information: Protective responses to sublytic complement in the retinal pigment epithelium, www.pnas.org/cgi/doi/10.1073/pnas.1523061113

Related Stories

Study reveals mechanisms of dry age-related macular degeneration

November 5, 2014
University of Kentucky researchers led by Dr. Jayakrishna Ambati, professor and vice-chair in the Department of Ophthalmology and Visual Sciences at the University of Kentucky, have made revealing discoveries about the precise ...

Team finds novel approach to treating age-related macular degeneration

November 10, 2014
While oxygen is essential to our planet's life force and the way we function and stay healthy, high concentrations referred to as oxidative stress may very well be the cause of more than 70 widely-spread diseases such as ...

New hope for patients with macular degeneration

December 13, 2013
Macular degeneration is a leading cause of blindness in Australia, affecting one in seven people over the age of 50.

Study suggests stem cells may repair dying retinal cells

January 21, 2016
Researchers at St. Erik Eye Hospital and Karolinska Institutet have for the first time successfully transplanted human retinal pigment epithelial cells derived from stem cells into eyes that are similar to human eyes. The ...

Recommended for you

In effort to treat rare blinding disease, researchers turn stem cells into blood vessels

February 13, 2018
People who inherit a mutated version of the ATF6 gene are born with a malformed or missing fovea, the eye region responsible for sharp, detailed vision. From birth, their vision is severely limited, and there is no cure. ...

Antioxidant therapy prevents devastating vision loss when added to standard-of-care on rare birth defect

February 5, 2018
A new study led by vision researchers at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo and VA Western New York Healthcare System has demonstrated that the addition of widely available ...

Genetic basis for glaucoma uncovered

January 30, 2018
In two recent publications, Northwestern Medicine scientists and international collaborators discovered mutations that cause improper drainage and a buildup of ocular pressure leading to one form of congenital glaucoma, and ...

Study advances gene therapy for glaucoma

January 16, 2018
While testing genes to treat glaucoma by reducing pressure inside the eye, University of Wisconsin-Madison scientists stumbled onto a problem: They had trouble getting efficient gene delivery to the cells that act like drains ...

New study offers added hope for patients awaiting corneal transplants

January 9, 2018
New national research led by Jonathan Lass of Case Western Reserve University School of Medicine has found that corneal donor tissue can be safely stored for 11 days before transplantation surgery to correct eye problems ...

Diabetic blindness caused and reversed "trapped" immune cells in rodent retinas

January 3, 2018
Johns Hopkins researchers have discovered a cell signaling pathway in mice that triggers vision loss in patients with diabetic retinopathy and retinal vein occlusion – diseases characterized by the closure of blood vessels ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.