Innovation in Retina

EDITED BY EMMETT T. CUNNINGHAM, JR., MD, PhD, MPH, AND PRAVIN U. DUGEL, MD

Dr. Gregory Hageman and the Role of Complement in AMD

Unlocking the mysteries of retinal disease

JERRY HELZNER, CONTRIBUTING EDITOR

If Gregory Hageman’s bride had taken more of a liking to the isolation of living on rugged Catalina Island off the coast of California, the world would probably now have one more excellent marine biologist and one less brilliant researcher of retinal diseases.

Fresh from earning his PhD in marine biology from the University of Southern California in 1983, Dr. Hageman took a position as resident biologist at the Wrigley Marine Science Center on Catalina Island. One facet of the work that fascinated him early on was studying the eye spots of microscopic sea creatures. But when that post ended after six years, and to ensure domestic bliss, Dr. Hageman went back to his base at the USC School of Medicine and began focusing his research efforts on retinal cell biology. As he came into contact with more and more people who were afflicted with retinal disease, especially those with age-related macular degeneration, including his wife’s grandmother, he felt he could make a more immediate impact. “I decided to change my career path because of a strong desire to contribute to our understanding of AMD,” he said.

Gregory Hageman, MD, PhD, courtesy of John A. Moran Eye Center, University of Utah

THE MYSTERIES OF DRUSEN

Dr. Hageman felt a key to understanding pathways associated with the development of AMD might be gained by studying the deposits in Bruch’s membrane called drusen, which are a hallmark feature of AMD. At that time, in the early 1990s, the composition and origin of drusen remained a mystery, so he began his long, intense study of thousands of donor eyes in an attempt to unlock the secrets of this major cause of blindness. Based on a driving concept that there were no animal models of AMD, he built a repository of genetically and clinically characterized human donor eyes that is now comprised of more than 7,500 pairs. This unique repository — in combination with assessment of rigorously characterized patient-based cohorts — played a key role in the elucidation of AMD-associated pathways. Additionally, from this major effort Dr. Hageman gained a profound respect and appreciation for the many individuals who donated their eyes and selflessly provided such precious gifts for his research activities.

By the mid-1990s, his hard work began to pay off. While at Saint Louis University, he experienced a critical breakthrough: his studies of donor eyes suggested that drusen were comprised of proteins associated with the complement system and that aberrant function of the complement system at the level of the RPE-choroid interface plays a key role in disease etiology.

LONG, INTENSIVE RESEARCH

A second major breakthrough occurred after Dr. Hageman moved to the Carver College of Medicine at the University of Iowa, where he was the Iowa Entrepreneurial Professor. It was the observation that the complement was not being regulated in the back of the eye in individuals with AMD that led his team to the discovery of the first AMD-associated gene. He and his colleagues determined that variations of the Complement Factor H (CFH) gene — a gene that regulates the complement system — are strongly predictive of an individual’s increased risk of being afflicted with macular degeneration. A common haplotype of CFH and variations in another complement regulator, Complement Factor B (CFB), were shown to account for more than 50% of the risk for AMD. Three other groups made similar findings, providing near immediate and strong validation of this discovery. Importantly, protective haplotypes of CFH — one that contains a large, common deletion distal to CFH that encompasses the CFHR1 and CFHR3 genes — were also discovered by Dr. Hageman and his colleagues in 2006. Other researchers identified variants in the C3 and CFI genes as also having an association with AMD. Collectively, these discoveries provided strong support for the earlier paradigm proposed by Dr. Hageman and colleagues that AMD is a byproduct of inflammatory processes characterized, in part, by robust activation of the complement cascade in the ocular macula.

A former director of the Human Genome Project called the identification of the role of complement factors in retinal disease “The first major translational research discovery to come from the Human Genome Project.” Dr. Hageman’s work on the role of the complement system in AMD so impressed the National Institutes of Health that his team was awarded a five-year, $14.6 million NIH grant to investigate the specific roles of complement genes in the etiology of AMD.

Dr. Hageman further explained the basis of his research findings in the American Macular Degeneration Foundation (AMDF) magazine, noting that “activation of the complement system creates some ugly proteins that are meant to destroy bacteria and abnormal cells, but that in a number of diseases, such as Alzheimer’s and multiple sclerosis, where that system is not controlled appropriately, these proteins do as much harm to healthy cells and tissue in one’s own body as they do to bacteria and other organisms that it’s designed to kill — basically, you can imagine a situation in which Factor H doesn’t shut off when it needs to shut off, leading to a lot of damage to healthy cells and tissues,” he states. “In the case of AMD, the damage is to your macula, resulting in its destruction and ensuing loss of vision.”

THE STEELE CENTER FOR TRANSLATIONAL MEDICINE

In 2009, Dr. Hageman came to the John A. Moran Eye Center at the University of Utah, where he is currently John A. Moran Presidential Professor of Ophthalmology and Visual Science and Executive Director of the Sharon Eccles Steele Center for Translational Medicine (SCTM). With this move, he brought the largest known human eye repository and research laboratory transfer in the university’s history. Within the SCTM, Dr. Hageman and his colleagues bring together deep expertise in the biology, genetics, and clinical attributes of AMD, drawing upon the collective strengths and expertise of a collaborative team of cell biologists, geneticists, epidemiologists, molecular immunologists, pathologists, and ophthalmologists to expedite its translational mission. The SCTM draws upon a cadre of unique resources, including numerous, well-characterized, and genotyped patient cohorts, the human donor eye repository, the Utah Population Database, the state’s extensive genealogical records, and other robust partnerships and collaborations, to more rapidly develop tools to accurately diagnose AMD risk, monitor disease progression, identify gene-directed pathways and targets, and develop therapies for the treatment of AMD and related conditions.

In 2012, Dr. Hageman was a key figure in the formation of an academic/industry alliance between the SCTM, Voyant Biotherapeutics, and Allergan. Voyant was created in 2011 to efficiently capitalize the commercialization of scientific discoveries made within the SCTM and to facilitate collaborative commercial partnerships to identify and expeditiously validate new targets for AMD drug development. The goal of the partnership was for the two companies to work together to identify disease-associated pathways and targets for the development of new therapeutic agents to treat ocular disease. “Efforts over the first three years of the collaboration far exceeded the expectations of all three partners and provided the discoveries of important new targets for early-stage, dry AMD,” says Dr. Hageman. Actavis acquired Allergan in 2015, after which time the Allergan Research and Development team — an asset deemed critical to the Voyant-CTM-Allergan collaboration — was reduced by more than 80%. The Allergan partnership was terminated in October 2015, and the SCTM and Voyant are in late-stage negotiations with a new partner, a relationship that will benefit substantially from the collective assets developed by the SCTM over the past six years.

RESEARCH IS ON THE RIGHT PATH

For nearly 30 years, Dr. Hageman has committed his career to retinal research. Although primarily recognized for his discoveries related to AMD, his early scientific studies also contributed to our understanding of the interphotoreceptor matrix in retinal adhesion and photoreceptor viability, as well as the role of pharmacologic vitreous disinsertion in ocular diseases. Dr. Hageman has authored more than 130 articles and publications relating to his work, been awarded more than 100 patents, has briefed Congress several times on his findings related to AMD, and has founded two companies aimed at discovering new diagnostics and disease-modifying therapeutics to combat early-stage AMD. And he is acknowledged as the earliest pioneer in connecting the role of the complement system to the etiology of AMD.

“It has been a long, long laborious piece of work,” he told the AMDF magazine, in reference to validating the role of the complement system in retinal disease. “Fifteen years ago, even 10 years ago, many individuals thought we were well off base. There were many times that I considered leaving the field because of the unwillingness of colleagues to accept the concept that the complement system plays a major role in the AMD disease process. However, it is now clear that the complement system plays a major role in AMD, and I don’t think many would disagree at this point in time,” he says.

“At the end of the day, however, I look back and realize that I’ve had a wonderfully exciting career. I am so fortunate to have had the opportunity to associate with such talented colleagues and to have made life-long friends. And, to be sure, it’s comforting to have played a part in the discovery of AMD-associated genes and pathways. Most importantly, I will say to all those individuals who are afflicted with AMD, know that the future is bright — there’s a lot of current activity in the development of therapeutic agents being designed to regulate the complement system in AMD, and the day will come that one or more of these agents will be found to delay the progression of this devastating condition.” RP