New treatment target identified for type 2 macular degeneration

A new study in mice offers promise as a possible alternative treatment option for the “wet” version of age-related macular degeneration (AMD).

Researchers have determined in mice that an enzyme related to cell growth and division is responsible for the invasion of blood vessels at the back of the eye that causes blurred central vision in wet AMD. Targeting the enzyme, called telomerase, with an experimental drug suppressed the abnormal vascular growth in the animals' retinas.

The only current treatment for wet AMD is injection into the eye of a drug that blocks the activity of a growth factor protein, called VEGF, which is also known to cause abnormal blood vessel growth in this disease.

“Anti-VEGF therapy has shortcomings: After two years, about half of people no longer respond to treatment. And patients can develop scars under the retina,” said the study’s lead author, Nagaraj Kerur, associate professor of ophthalmology and visual sciences at The Ohio State University School of Medicine.

“There is a need to better understand the mechanisms behind this problem, which to me means that new targets need to be tested.”

The study was recently published in the journal Biochimica et Biophysica Acta – Molecular Basis of Disease.

Dry age-related macular degeneration makes up about 80% of all AMD cases and occurs when the macula, part of the retina, thins, leading to protein buildup and cell death, blurring a person's central vision.

Wet AMD, also known as neovascular AMD, is caused by the growth of new blood vessels that invade the retina, a space normally free of vascular activity.

“You don’t want to have blood vessels there,” said Kerur, who is also a professor of microbial infections and immunity at Ohio State University. “And the blood vessels that invade the body are often not healthy: They leak their contents and cause inflammation.”

Previous cancer research has linked high telomerase activity to the rapid production and migration of cells lining blood vessels, which enables tumor growth, and has also shown that the enzyme can stimulate the production of VEGF. Based on these findings, Kerur and colleagues sought in this study to see if telomerase could have a similar harmful effect in the eye.

A series of experiments confirmed for the first time the role of telomerase in the abnormal formation of blood vessels in a mouse model of wet AMD. The researchers found that, compared with control mice, the expression and activity of one of two genes carrying the instructions for telomerase production was higher in the eyes of mice in which rapid growth of new blood vessels had been induced by a laser.

Additionally, the abnormal blood vessel response to laser injury was significantly lower in mice lacking both telomerase genes, “providing genetically clear evidence that telomerase plays a critical role in disease development,” Kerur said.

The team then tested the effects of an experimental compound that inhibits telomerase activity. They confirmed that the drug decreased telomerase activity in healthy mice and found that injecting the drug into the eyes of mice with symptoms mimicking wet AMD significantly reduced abnormal blood vessel invasion.

Telomerase works to rebuild telomeres, which function like protective caps at the ends of chromosomes. Telomeres are known to shorten in many cell types as we age, but Kerur said the study suggested that blocking telomerase locally in the eye did not affect the enzyme’s telomere-building function.

The effectiveness of the experimental treatment in curbing abnormal blood vessel growth in mice was similar to that of current anti-VEGF therapy, Kerur said. But the researchers made an intriguing discovery when they tested both drugs at lower doses: Individually, a lower dose didn't have much therapeutic effect, but a combination of the two drugs at lower doses produced the best results of all.

“One goal might be to use a combination therapy rather than just one,” Kerur said. “But telomerase inhibition itself can also be pursued independently, and that’s what’s planned.”

This work was supported by grants from the National Institutes of Health, the Ohio Lions Eye Research Foundation, and a Prevention of Blindness Research Grant.

Co-authors include Aman Kumar, Vinodhini Jayananthan, Asmaa Zidan, Tyler Heisler-Taylor and Shigeo Tamiya of Ohio State, and Yosuke Nagasaka and Jayakrishna Ambati of the University of Virginia.