John A. Moran Eye Center: Be Undaunted by Gregory S. Hageman, PhD

John A. Moran Eye Center

Be Undaunted

By Greg Hageman, Moran Eye Center A version of this article appeared as the October 2013 cover story for The Ophthalmologist magazine.

Gregory Hageman, PhD, John A. Moran Presidential Professor, Department of Ophthalmology and Visual Sciences, and Executive Director, Moran Center for Translational Medicine (CTM) in Salt Lake City, Utah, is among the most respected ophthalmic researchers in the world.

Medical textbooks include his findings, and he’s addressed Congress three times. In 2005, the National Institutes of Health awarded Dr. Hageman and his colleagues a $14.8 million grant to study age-related macular degeneration (AMD)—one of the largest ever awarded to ophthalmic research of any kind.

Dr. Gregory Hageman selects an eye from one of 18 refrigerators containing 8,000 eyes from human donors.

The depository has played a critical role in breakthrough discoveries in eye disease.

A

ge-related macular degeneration (AMD), a leading cause of worldwide blindness, is one of the most wellcharacterized genetic diseases. Remarkable advances in our understanding of the disease have come about through recent scientific and clinical data, including the discovery of two genetic regions that are responsible for the majority of AMD risk. Age-related macular degeneration is typically described as a single, complex disease. Importantly, however, our recent observations suggest that AMD may indeed be multiple, distinct biological diseases that exhibit significant overlap in the population. We have noted striking differences in the presentation, progression, and biology of this disease in distinct, genetically defined subgroups of AMD patients. By studying groups of patients with differing genetic susceptibility to disease, we aim to develop a deeper understanding of the biology that underlies different forms of AMD and the pathways that are specifically associated with AMD-associated genetic risk.

One major goal of our studies is to identify, particularly among patients with early-stage AMD, those at the greatest risk of developing severe visual loss in the future. Other important longer-term goals of our research efforts are being directed toward the development of disease-directed diagnostics, the stratification of patients for future clinical trials, the identification of drug targets, and the development of effective therapeutics for distinct forms of this devastating disease.

To date, our team has collected more than 6,000 pairs of eyes from human donors, most with detailed patient histories and genetic profiles. (The next largest collection in the world is just a few hundred). This repository has made it possible for us to identify important new AMDassociated pathways that we hope will lead to the development of drugs to treat the earliest stages of AMD, drugs that could save the next generation from blindness. And, we hope to accomplish this in a shorter time than it would take a pharmaceutical company, through Moran’s Center for Translational Medicine (CTM). Certainly an audacious goal, but the Moran family—a close community of clinicians, scientists, technicians, patients, donors, and hundreds of other supporters who have joined the fight for better vision care and medicine—is up to the challenge.

“I love a good scientific debate!

In fact, I cherish it. In the end, perseverance and strong Overview of Current Research Our recently adopted strategy of elucidating biologiscience always win the day.” cal pathways and therapeutic ‘targets’ in patients and donors with reticular pseudodrusen (RPD)-, chromosome 1-, and chromosome 10-directed AMD has provided tantalizing new information suggesting that AMD may be multiple, distinct biological diseases that exhibit significant overlap within the population.

However, it is important to note that more extensive studies will be required to validate this important, novel concept. Our current studies are designed to further illuminate the clinical phenotypes, histology, and biology of RPD-, chromosome 1-, and chromosome 10-directed disease and to test the concept that AMD is distinct biological diseases. We anticipate that these studies will ultimately provide a comprehensive understanding of the role of risk conferred

by RPD, chromosome 1, and chromosome 10 on AMD pathology.

This ‘multiple disease’ concept is based on a corpus of solid scientific data. This novel concept will certainly challenge the field, and I believe the responsible thing to do is to challenge current dogma—something I’ve done most of my career. At the end of the day, our concepts may be proven right or wrong, but the challenge will make colleagues dig deeper, ask more rigorous questions, and discover facts about the disease. That’s what dedicated scientists do—we can debate strongly, and at the end of the day, science will win the day.

Cross section of a retina from a patient with a history of AMD, showing round abnormal deposits called drusen starting to form.

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Multiple

AMD

phenotypes

Beginnings: Building a Human Eye Depository

I became interested in eye anatomy and vision during my first job as the Director of Research at the University of Southern California’s Marine Biology Station off the coast of California. That was 1983. I made $8,000 a year, had a boat, wore shorts to work, and went diving every day. I loved it. I became fascinated by invertebrate eyes and the eye spots of bryozoans, tiny sea creatures that live in colonies similar to coral colonies. Soon thereafter, however, I was offered a faculty position and pursued my first research in the field of glaucoma.

At about that same time, my wife’s grandmother, who lived to be 100, was in great health except that she developed AMD. Scientifically and clinically, there was nothing being done about AMD at the time. It was often referred to as senile macular degeneration, a terrible term in my opinion. I turned a glaucoma grant into an AMD grant and never looked back. From there, we moved to St. Louis University where I was tasked to build the research component of the Anheuser Busch Eye Institute.

It was during this time that we developed the concept of using eyes donated at the time of death to reveal pathways associated with the development of AMD. The general concept was a simple one: could we acquire enough eyes from patients who had clinical histories of AMD and compare them to patients who didn’t have the disease in order learn something about the AMD diseaseassociated processes at the back of the eye?

We started with a straightforward question related to the abnormal deposits, called drusen, that form in the back of the eyes of individuals with AMD. We wanted to know what these deposits were comprised of, and where they came from. We reasoned that we could gain new insights into the disease process if we could answer these questions. Although the questions have changed over time and our technical capabilities have improved, this approach has been a pivotal component of our work to this day.

I will always be extremely grateful to all the individuals and families for the precious gift of these donated eyes. I have spent thousands of hours with the families who donate eyes and learned how incredibly unselfish these gifts really are.

I have learned a lot of humility and will always be a respectful steward of this valuable resource.

During the ten years I spent in St. Louis, my colleagues and I discovered that drusen were comprised largely of components associated with the complement system, an important component of innate immunity. These findings provided distinct lines of evidence that implicated a role for chronic local inflammation and activation of the complement cascade in AMD pathogenesis.

I learned another lesson in St. Louis that has driven my career: the idea that pharmaceutical companies and academics could, and should, work together collaboratively in order to expedite the development of therapies for this devastating disease. We have enjoyed wonderful collaborations with pharmaceutical companies over the past 25 years. These interactions certainly helped later on, as we were developing the conceptual framework of the CTM and validating its philosophy and mission.

Dr. Hageman and Dave Hutcheson, a Research Scientist at the Moran Eye Center, discuss the progress of a new collaboration with multiple University of Utah

Discovery

scientists and clinicians.

Iowa: Expanding the Science

I went to Iowa to help set up a Center for the Study of Macular Degeneration, which is thriving to this day. We also started an eye donation process from scratch. I continue to be in awe at the generosity of all those who choose to donate, as well as all the individuals who give of their time to make this process work. I cherish all the memories of this process; one in particular comes to mind. In a very small town in Iowa, I met a remarkable woman, Mrs. P, whose husband passed away a few days before Christmas. She said “Dr. Hageman, we want to take up a collection for your research.” Three months later, I received a card signed by 250-300 people—almost the whole town—with a check for $72.83, donated to our research program. That donation was pretty special. It wasn’t about the money—it was about the wonderful people you meet in the process.

The years spent in Iowa were extremely rewarding scientifically. We validated our concept that the complement system was involved in the etiology of AMD by the discovery of a significant association between AMD and variants of key complement pathway-associated genes. Based on these discoveries, I was the scientific founder of Optherion, Inc., an early stage biotechnology company focused on developing a platform of diagnostics and therapeutics for the treatment of AMD and other chronic diseases and conditions involving the complement alternative pathway. Optherion closed on a $38 million start-up Series A financing round in July 2007.

A core element of this company was an intellectual property portfolio developed by colleagues all over the country. We formed a consortium that was managed by the University of Iowa—the right approach and another lesson.

The Factor H discovery indicated that abnormalities in Factor H-mediated regulation of the alternative pathway of the complement cascade were likely involved in a large percentage of all AMD cases. We proposed that the risk forms of Factor H give rise to quantitative or functional alteration(s) in the CFH protein, specifically including CFH’s ability to bind to CRP, heparin, and other proteins involved in the alternative complement pathway. This, we postulated, results in uncontrolled complement activation and bystander injury to the macula, resulting in its degeneration and an associated loss of vision. Thus, a key premise upon which Optherion was based was that the replacement or augmentation of the complement modulating activity of the dysfunctional CFH protein should be effective in preventing or delaying the pathology associated with AMD. Simply put, Optherion’s approach was to provide back the protective form of Factor H via systemic injection, similar in concept to insulin therapy for the treatment of diabetes. I still believe this is a solid scientific approach; time will tell us whether this approach will slow or halt the progression of early stage AMD.

life

A Passion for Life and People I was raised in Central California, where my ancestors homesteaded as cotton farmers in 1885. I grew up listening to my great grandparents’ stories about outlaws with guns coming into town. I spent time on the farm: family dinners, the outdoor toilet, catching frogs and snakes. It’s where I learned to fish and hunt.

During cotton season—picking season, the whole family showed up. I was about five-years-old, but I picked cotton. I was allowed to roam, to play, and to wonder.

You learn a lot about life through these experiences, a lot that remains with you and guides your future efforts and activities. My wife, Jill, grew up in the same town. I went to high school with her. Of course, everybody wanted to take her out, so there was no hope for me. Later, when I was in graduate school, I went home for a weekend, reacquainted with her at a local drug store, and begged her for a date. That was it—we fell in love, have been happily married for almost 35 years, and been blessed with two fantastic children. These collective experiences instilled in me a sincere passion for life and for people and formed the philosophical foundation for the way in which I would conduct my life.

Randall J Olson, MD, Professor and Chair of Ophthalmology and Visual Sciences, CEO, John A. Moran Eye Center, consulting with Gregory Hageman, PhD, John A. Moran Presidential Professor of Ophthalmology and Visual Sciences and Director of the Moran Center for Translational Medicine.

Collaboration

Salt Lake City: A New Opportunity Around this time, I met Randy Olson, MD, Professor and Chair of Ophthalmology and CEO of the Moran Eye Center in Salt Lake City, and he offered me a job. I politely said ‘no,’ as I was convinced that I was destined to work in the pharmaceutical world. But the more I thought about it, the more I realized that academics provides access to important resources that pharmaceutical companies do not typically have—human donor eyes, study patients, populationbased databases, and the like.

One day, Randy asked me what I wanted to do with the remaining years of my career. I replied, “I want to cure this disease in my lifetime.” He responded, “Then let’s do it.” So, we created the CTM to expedite the pace at which basic scientific discoveries are translated into clinically effective diagnostics and therapies for the treatment of AMD and its co-segregating diseases. The conceptual framework for the CTM derived from a growing realization that seemingly disparate diseases likely share common etiologies and thus, common therapeutic targets. The CTM draws upon the collective strengths and expertise of an interdisciplinary, collaborative team of over 50 cell biologists, molecular immunologists, geneticists, microbiologists, pathologists, and clinicians to expedite its translational mission. The general concept of the CTM is that its unique resources and strong clinical and scientific expertise will complement the core competencies of collaborating corporate and academic partners to ensure its success. The CTM is a true embodiment of the Moran Eye Center Mission Statement that “no person with a blinding condition, eye disease, or visual impairment should be without hope, understanding, and treatment.”

What We Are Accomplishing at the CTM

Over 1,000 pairs of eyes have been donated to the CTM repository during the past three years. We have launched an expanded effort to recruit currently enrolled study patients to become eye donors upon their deaths. Importantly, 22 percent of our donors were previous patients seen at the Moran Eye Center, thus providing us with the unique capability to establish links between genes and how the disease expresses itself (phenotype) in a way that most researchers cannot.

Data derived from these tissues, combined with that derived from patient cohorts, plays a critical role in the identification of key AMD-associated genes, pathways, and therapeutic targets. Medical and ocular histories, a family questionnaire, blood, and sera are obtained from every donor. A database of ophthalmological, medical, and scientific information related to each donor has been and will continue to be maintained. Approximately 24 percent of the eyes in the collection have verified clinical histories of AMD, and numerous other, well-documented ophthalmic and systemic diseases are represented in the repository. A variety of resources including DNA, RNA, protein, fixed tissue, and fresh-frozen tissues are routinely prepared for experimental analysis.

Unique Resources: Clinical Cohorts Healthy Retina

Retina with AMD

A normal, healthy human retina. The dark central area is the macula, the structure responsible for all finely detailed sight at the center of our field of vision.

The retina of a patient with macular degeneration, with visible damage around the macula.

Our CTM cohort of AMD case and control subjects is currently comprised of approximately 3,500 Utah study patients with and without AMD and an additional 20,000 study patients from other locations and of a variety of ethnicities. Medical, ophthalmological, and imaging data, as well as DNA, serum, plasma, and urine is available for most of these study patients; these resources are critical for coordinated genomic, proteomic, epidemiologic, and other studies.

We continue to recruit study subjects, focusing on refining the existing cohorts and adding subjects with the reticular pseudodrusen (RPD) phenotype. We currently have DNA samples from over 700 individuals with RPD in the collection.

Our current focus is to dissect chromosome 1- and chromosome 10-associated pathways, to clinically evaluate disease progression driven by these genes, and to identify gene-specific ‘targets’ upon which to base future drug development efforts.

Dr. Hageman analyzes sections of eye tissue donated to his AMD research.

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Vision

Where Things are Going Now

Right now, I have the most talented people working for me that I’ve ever had in my life. In addition to the clinical and research faculty and staff members of the CTM, we’ve hired six people into the lab who have industry expertise in drug development—people who have never worked in academics before. Collectively, that group of people has over 100 man-years of experience. There are four teams in the CTM: a Clinical Resource Team, a Biological Resource Team, a Target Discovery Team, and a Target Validation Team. I’m extremely proud of these teams and the data they are generating.

Selecting a pharmaceutical partner is the next important piece of the plan, a partner we can work side-by-side with as we identify and validate gene-directed targets for new AMD treatments. With a true industry partnership, we can shorten the drug development delivery time by years. We are currently in discussions with a number of potential partners and will likely select one in the next few months.* So that’s the dream—and because of the team and resources we’ve assembled, I have little doubt that we will accomplish our ultimate goal to halt or delay the progression of this blinding disease. We have already identified some critical pathways associated with the disease, and our momentum is strong. To be clear, we could not have accomplished all this without the support of Randy Olson— who is so uniquely special—our Moran family, and the wonderful collaborative relationships we enjoy with individuals all over the world. Indeed, we are indebted to my colleagues from Africa, Ireland, England, France, China, Japan, Chile, Ghana, Iran, Austria, Australia, and all over the US for their strong support. And, I will be forever grateful to all those patients, donors, and families for their unselfish gifts to our program. Their hope that we will be successful in our endeavor drives us to push even harder. In the end, it will be the science and all the individual people who have helped along the way that will help us to win the day. We will find a cure for AMD in my lifetime—all of us, working together. *Update: In January 2014, the final exciting piece was put in place: the John A. Moran Eye Center announced that Voyant Biotherapeutics, LLC, a company formed out of the Moran CTM, signed an exclusive R&D collaboration agreement with Allergan, Inc. (NYSE: AGN), a multi-specialty health care company headquartered in Irvine, California. The first partnership of its kind at the University of Utah, the agreement brings top retinal research teams in academia and private industry together to focus on the common goal of fighting AMD. “Allergan brings complementary resources and expertise to the table, as well as a cohesive, accomplished retinal research team and a proven track record in the advancement of novel therapeutic agents into clinical practice,” says Dana Ono, PhD, CEO, Voyant Biotherapeutics.

“We believe this will be the beginning of a fruitful partnership.”

John A. Moran Eye Center | 65 Mario Capecchi Drive Salt Lake City, UT 84132 | 801.581.2352 | www.moraneyecenter.org