By accelerating the aging process of stem cells from patients, researchers at P&S have created a model of age-related macular degeneration in a dish and have used the model to learn why some people develop the disease.
Age-related macular degeneration (AMD) affects 9 million Americans and is one of the leading causes of vision loss in people over 50. The disease progressively destroys cells in the retina’s macula, which is responsible for our ability to see details in the center of our vision.
Though effective treatment exists for the less common “wet” form of AMD, there are no treatments for the more common “dry” form because the disease is difficult to study in the laboratory.
The new patient-specific disease model, created by Janet Sparrow, PhD, and Stephen Tsang, MD, PhD, in the Departments of Ophthalmology and Pathology & Cell Biology provides scientists with a way to better understand how the disease progresses, screen for drugs that can prevent or slow the disease, and potentially develop personalize treatment. The findings are published online in the journal Human Molecular Genetics.
The unique structure of the human eye is one reason why scientists struggle to study the dry form of AMD. “Mice do not have a macula in their eyes, so there is no animal model for the disease, Additionally, we cannot remove eye tissue from living patients, so we can study eyes only from deceased patients, who usually have advanced disease,” says Dr. Tsang, who is the Laszlo Z. Bito Associate Professor of Ophthalmology and associate professor of pathology and cell biology.
“We need to study eye cells in the initial stages of the disease so we can devise treatments to prevent vision loss. Patient-specific stem cell lines give us that opportunity.”
In creating the model of AMD, Dr. Tsang and his postdoc Jin Yang, MD, PhD, took skin cells from several patients who carry genes that increase the risk of developing AMD. Drs. Tsang and Yang converted these skin cells to stem cells and then to retina cells.
However, retinal cells made from such stem cells act like young eye cells and do not show signs of degeneration. “Other groups have made retina cells this way and have tried to compare them with cells made from people with healthy eyes, but they’ve found no differences,” Dr.Tsang says.
The key advance by the Columbia researchers is a method devised by Dr. Sparrow to accelerate the aging process of the stem cell-derived retina cells.
“To the retina cells we added debris products of vitamin A—which accumulate in the eye over decades of normal aging—and we exposed these cells to the equivalent of sunlight,” Dr. Tsang says. “After 10 days, by most criteria, the cells then behaved like 60-year-old cells.”
By comparing aged retina cells from AMD patients with those from healthy controls, the researchers discovered why the patients had developed the disease.
“The eye is constantly exposed to light, and that produces lots of damaging oxygen radicals that build up in the eye,” Dr. Tsang says. “We found that in AMD patients, the eye cannot protect itself from oxygen radicals because an antioxidant defense enzyme inside the eye—called SOD2—does not work well.”
That means compounds that increase SOD2 activity may be effective at preventing cell death and vision loss in people who carry genes linked to AMD.
The Columbia team’s effort of creating patient-specific cells and “AMD in a dish” may be critical to finding such drugs. “Instead of testing each drug candidate on thousands of patients, it will be easier and faster to screen for drugs on a couple of thousand cell lines to see which ones have the greatest potential,” Dr. Tsang says.
Ultimately, the cell model also may be used to personalize treatment of the disease. “For people who don’t have the disease but have a high genetic risk, we can take their skin cells, make them into retinal cells, age them, and then find the drug that is the most likely to prevent macular degeneration and vision loss in that individual.”