Patient registry holds promise for age-related macular degeneration discoveries

May 30, 2019
Image demonstrating how research is being done for age-related age-related macular degeneration.
Tara Churney, a senior profession research assistant for the Division of Ophthalmic Epidemiology, processes a blood sample for AMD registry’s biorepository. Photo courtesy of Anne Lynch.

Researchers on the UCHealth Anschutz Medical Campus believe that deepening repositories of electronic data could help shine a light on a disease that dooms millions of people to fading vision.

The data comes from patients with age-related macular degeneration (AMD), which affects some 11 million people in the United States. The disease disrupts the functioning of the retina, the area at the back of the eye that is responsible for receiving light through photoreceptor cells. These cells convert the light to electrical impulses, which they pass along a cell network to the optic nerve and on to the brain. The disruption deteriorates vision and for many leads to blindness.

In 2014, the University of Colorado School of Medicine’s Department of Ophthalmology launched the Division of Ophthalmic Epidemiology. The goal: probe the roots of age-related macular degeneration and spur research that could lead to new treatments for the disease. The division’s research is bolstered with a $5 million gift that established the Frederic C. Hamilton Macular Diagnostics Center at the Sue Anschutz-Rodgers Eye Center and a $300,000 challenge grant to the Department of Ophthalmology from Research to Prevent Blindness.

Everybody into the data pool

The Division of Ophthalmic Epidemiology laid the foundation for new age-related macular degeneration research in 2015 with a registry that today contains the medical records, imaging data and blood specimens of more than 1,000 patients with the disease. All of them receive their care at the UCHealth Eye Center. The registry also includes control data from patients who have cataracts but do not have AMD, said Dr. Anne Lynch, professor and director of the division, which includes a biostatistician, an epidemiologist and five professional research assistants.

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Dr. Anne Lynch directs the Division of Ophthalmic Epidemiology, which launched a registry of patients with age-related macular degeneration (AMD) in 2015. Photo by UCHealth.

The registry recruitment of the past four years is ready to pay off, Lynch said.

“We’ve been very successful with our recruitment and now have the process streamlined,” she said. “We are now at the point where we can do research.”

For example, Lynch pointed to a grant from the Macula Society for proteomic studies that analyze the proteins expressed by cells and tissues in patients with early- or intermediate-stage, age-related macular degeneration. The Eye Center is also site for a National Eye Institute research grant that targets early-stage AMD patients. The Division of Ophthalmic Epidemiology and its partners have published or have under review several papers that examine the factors that may contribute to AMD, including an article in the journal Retina published in 2018 that described the formation and goals of the registry as well as insights gleaned from it.

In addition, the registry team now plans to collect a blood sample and images from patients once a year, a key to finding changes that offer clues to the progression of age-related macular degeneration.

“We’re looking for patients to study before they convert to the advanced form of the disease,” Lynch said.

Looking for light

Those patients could shed new light on a disease that has so far remained stubbornly resistant to treatment. There are two types of age-related macular degeneration. About 10 percent have the “wet” form, which causes new blood vessels to grow abnormally in the retina and the retinal pigment epithelium (RPE), a covering of cells that nourishes and cleans the retina. Providers can treat wet AMD with injections that slow blood vessel growth. Geographic atrophy, or “dry” AMD, affects the vast majority of patients. Dry AMD causes cells to die in the retinal pigment epithelium. Without retinal pigment epithelium support, the photoreceptors atrophy and die, leading to vision loss and irreversible blindness.

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The detailed data in the patient registry is key to discovering therapies for AMD, says Dr. Naresh Mandava, chairman of the Department of Ophthalmology at the University of Colorado School of Medicine. Photo by UCHealth.

There is as yet no treatment for the dry form of age-related macular degeneration and one isn’t likely to come along without the kind of data the registry provides, said Dr. Naresh Mandava, a retinal specialist and chair of the Department of Ophthalmology at CU.

“The problem we have with drug therapies for AMD is that we have not yet identified the patient population that will rapidly progress,” Mandava said.

The registry vastly improves the odds of finding them, he added. Data from it could reveal, for example, unusual levels of specific proteins or molecules that accelerate the progression of the disease in some patients and not others. Such discoveries point to “the potential path of figuring out the cause of AMD” and developing targeted therapies, Mandava said.

“It’s a true discovery opportunity,” he said.

Complementary research

Image demonstrating how research is being done for age-related age-related macular degeneration.
Thuy Ton, a technologist at Exsera BioLabs, performs a test to measure complement proteins in blood samples. Such testing is shedding light on the contributors to age-related macular degeneration. Photo courtesy of Exsera BioLabs.

The opportunities are more than speculation. Registry data is fueling research of the body’s complement system in developing age-related macular degeneration. The complement system is a complex of proteins that helps the body fight infection, in large part by triggering inflammation. That’s a good thing when the body is warding off microbial invaders but if the complement system for some reason malfunctions, the resulting cascade of inflammation-triggering proteins can damage tissue in various parts of the body including, potentially, the retina.

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Rheumatology Division Head Dr. V. Michael Holers works with the AMD patient registry to analyze proteins that may contribute to the disease. Photo by UCHealth.

“The complement system is very pro-inflammatory,” said Dr. V. Michael Holers, head of the Division of Rheumatology at the CU School of Medicine and an expert in the workings of the complement system. “The system itself doesn’t discriminate between tissues when it causes damage. The target could be the joints, the eyes, the brain or the skin,” Holers said.

Research suggests that inflammation, improperly triggered, is the bridge from the complement system to age-related macular degeneration, Holers said. “The idea is that dysregulation of the complement system causes inflammation that kills cells in the back of the eye,” he explained.

Holers serves as clinical research consultant for the Division of Rheumatology’s Exsera BioLabs, which specializes in measuring complement proteins in small volumes of liquid, including fluid from the eye. In his role with Exsera, Holers and his colleagues collaborate with Lynch and Mandava, analyzing panels of proteins in samples collected from patients in the age-related macular degeneration registry. The lab work has contributed to studies of AMD and other retinal eye diseases.

Targeting inflammation

Lynch, who acknowledged that genetics and other factors, notably cigarette smoking, are among many culprits in age-related macular degeneration, said the collaboration with Exsera has opened new research doors.

“Genetics doesn’t tell the complete story of AMD,” she said. “We are trying to see if AMD is a systemic disease. What we’ve shown so far is that for sure these patients have markers of inflammation.”

That finding is only the beginning of a long road to offering patients hope. “We’ve identified complement abnormalities and are working to refine our understanding of the complement system in AMD,” Holers said. That effort is essential to one day developing therapies that block cell signaling that triggers the inflammation caused by specific complement proteins implicated in age-related macular degeneration.

It requires a nuanced therapeutic approach, not an all-out assault on the system. As Holers put it, “In a complicated pathway like complements, where do you apply ‘the hammer?’” But the therapeutic question is not only where to apply the hammer but when, he added.

Image demonstrating how research is being done for age-related age-related macular degeneration.
Exsera Biolabs, part of the CU Division of Rheumatology, tests fluids from AMD registry patients for proteins that trigger inflammation. Photo courtesy of Exsera BioLabs.

“The work with the registry has provided insights as to the appropriate therapeutic approach and at what time to introduce complement inhibitors during the very long course of AMD development,” he said. “It points to the importance of using inhibitors much earlier than has been used to date.” It also underscores the importance of using registry data to study important changes of many kinds in those patients who progress to the advanced form of age-related macular degeneration, as Lynch noted.

Holers and Mandava also stressed the importance of using samples from human patients with the disease. Holers called the registry “one of the fundamental tools that we use in modern biomedical research to make advances that are really directly related to patients. Traditionally we have used animal models, which are only approximations of the truth.”

Eying the mysteries of disease

The registry is accomplishing the heavy data lifting necessary to make transformational clinical discoveries, Mandava said. There will be no short-term fixes for age-related macular degeneration, which in the years ahead is on course to affect millions of more people in a steadily aging population, he added.

“It’s not easy to take thousands of patients and follow them for five to 10 years,” he said. “Academia has to do it.” Without extensive registry data, he added, drug companies can’t be expected to “take more long shots on goal” with expensive trials with highly uncertain outcomes.

The research from the registry, Mandava concluded, might develop relatively slowly but will strike at the most fundamental question of all: What is age-related macular degeneration?

“If you don’t know the discovery part, you’ll never be successful in developing a therapy,” Mandava said.



About the author

Tyler Smith has been a health care writer, with a focus on hospitals, since 1996. He served as a writer and editor for the Marketing and Communications team at University of Colorado Hospital and UCHealth from 2007 to 2017. More recently, he has reported for and contributed stories to the University of Colorado School of Medicine, the Colorado School of Public Health and the Colorado Bioscience Association.