Researchers look to immune system in combating dry AMD

Lois Sims said she would be still working today if macular degeneration had not dimmed her eyesight. Driving, required as part of her job with a law firm, became increasingly difficult as her condition progressed.

Sims, who has advanced dry AMD, also struggles doing some of her favorite hobbies, such as needlecraft and crossword puzzles and has trouble distinguishing colors. “I have magnifying glasses in every room in the house,” she said.

But the 74-year old Salem, Ore. resident is also encouraged by the abundance of research taking place to fight this disease. A patient at OHSU Casey Eye Institute’s Wold Family Macular Degeneration Center, Sims has participated in a number of clinical trials aimed at understanding dry AMD’s origins and slowing its progression. AMD runs in her family, she said, and her son is already showing signs of the disease.

Unlike wet AMD, which can be treated with injectable medications, proven therapies for the dry type remain elusive.

“Because the vast majority of AMD patients have the dry form there is an urgency to find effective treatments for the millions of patients like Lois who are currently affected or who face future vision loss,” said retina specialist Christina Flaxel, M.D., director of the Wold Family Macular Degeneration Center.

AMD is a complex condition influenced by a combination of genetic and environmental factors, such as smoking and diet. Although dry AMD usually progresses more slowly than the wet type, a small percentage of patients such as Sims go on to develop advanced disease, also known as geographic atrophy or GA.

“With geographic atrophy, patches of tissue in the central part of the retina, or macula, begin to deteriorate and eventually damage central vision,” said Flaxel. People with this late-stage condition can have difficulty reading, driving, seeing faces and doing other everyday tasks that require fine, detailed eyesight.

Keeping the immune system in check

Some of today’s most promising research is focused on a component of the immune system called the complement system, which is tasked with fighting off foreign invaders in your body, such as bacteria and viruses. Surprisingly, this part of the immune system has been detected in drusen, the fatty deposits that develop in the retinas of people with AMD.  While once thought to be only inactive debris and waste, “there is good evidence that drusen contain a large amount of complement proteins and are more active than previously suspected,” said Casey retina specialist Brandon Lujan, M.D., describing it as a “low-grade, simmering inflammation” which can’t be detected in an eye exam.

Gene discoveries support the involvement of the immune system in AMD. In the past several decades, scientists have identified certain gene variants in the complement that are associated with a higher risk of advanced AMD.

Flaxel is leading Casey’s participation in a new international study to learn how dry AMD develops over time in people with geographic atrophy who have a rare gene mutation in the complement system. Patients who qualify for the clinical trial, called GTSCOPE, will be followed for two years and then possibly be eligible to enroll in a clinical trial of a gene therapy.

The data gathered from this large-scale study will help develop future dry AMD research and treatments, according to the study’s sponsor, Gyroscope Therapeutics.

Earlier studies at Casey and other research sites also have focused on the complement system, such as the multi-center clinical trial of the investigational drug lampalizumab, in which Sims participated. The study medication was designed to inactivate an enzyme in the complement system implicated in the development of dry AMD. Although early results from the Phase 2 study were positive, the larger Phase 3 study was later suspended because it didn’t show an improvement in slowing down progression of advanced dry AMD. “Although it was a big setback, it doesn’t eliminate the strategy of addressing the immune system for the treatment of dry AMD,” said Lujan.

Currently, Lujan is principal investigator of another new dry AMD clinical trial called Gallego that targets a different enzyme in the complement system associated with advanced dry AMD. “What’s interesting is that this study medication, unlike the one in the lampalizumab study, doesn’t bind the target enzyme, but blocks its expression entirely,” he said.

A gut reaction?

While it is still unclear what causes the immune system to go into overdrive, scientists like Phoebe Lin, M.D., Ph.D., are pursuing some promising leads in novel ways. Lin, a specialist in retina and inflammatory eye disease at Casey, is studying whether changes in the diverse bacteria normally found in the intestinal tract – the intestinal microbiota - contribute to complement activation in dry and wet age-related macular degeneration.

Dr. Lin and her team are learning more about this complex interaction by comparing the microbiome of individuals with advanced AMD to those without the disease.

The researchers also found changes in the intestinal bacteria in study patients taking AREDS2 eye supplements and in those with certain gene mutations associated with AMD. These alterations may affect some of the biochemical pathways known to be involved in the disease, such as the immune system.

Based on these early findings, Lin has expanded her research and hopes it will eventually lead to new AMD treatments that target the intestinal tract.

Due to the current COVID-19 pandemic, enrollment in some AMD clinical trials may be temporarily suspended.

Learn more

Learn more about research studies at the Wold Family Macular Degeneration Center.