Moran Team Turning Genetic Discoveries Into Treatments For Age-Related Macular Degeneration

Mar 11, 2019 10:00 AM


Gregory S. Hageman, PhD, executive director of the Sharon Eccles Steele Center for Translational Medicine, in his lab.
Gregory S. Hageman, PhD, executive director of the Sharon Eccles Steele Center for Translational Medicine, in his lab.

For too long, hopes of a cure for age-related macular degeneration (AMD) have been elusive.

After more than 130 clinical trials to test potential AMD drugs over the past decade, the chronic condition remains the leading cause of blindness for more than 20 million Americans age 55 and over.

All the while, Gregory S. Hageman, PhD, and his research team at the John A. Moran Eye Center’s Sharon Eccles Steele Center for Translational Medicine (SCTM) have been quietly exploring the genetics behind AMD. Hageman refers to his team as “the most talented and enthusiastic group of people I’ve had the privilege to work with in my lifetime.” Their tireless efforts have translated a deeper genetic understanding into a new therapy that stands to change the outlook for AMD patients and their families.

A New Hope

Doctors have long characterized AMD as a single disease with two stages. Individuals with the early stage develop drusen—small, yellow deposits of a fatty protein that form under the macula, the region of the retina that supports seeing fine detail. In the later stage, the macula degenerates with or without the growth of associated abnormal blood vessels under the retina.

Hageman started his analyses of AMD in the late-1980s. He first assessed what drusen were made of, identifying a host of proteins associated with the complement system—a component of the body’s immune system that attacks invading cells and prompts inflammation. A decade later, he discovered a genetic link to AMD in a gene called Complement Factor H that regulates the complement system. Most recently, SCTM research has produced a Galileo moment for ophthalmology: AMD isn’t one biological disease. It’s at least two.

Complement system genes located on chromosome 1 cause one disease. An unrelated pair of genes found on chromosome 10 directs a second. Together, these two genetic regions account for more than 90 percent of genetic risk for developing AMD.

People with two copies of chromosome 1 risk genes, or homozygous carriers, are at significant risk for AMD. However, some people carry a form of the chromosome 1 gene that protects them from AMD. Those with one or two protective genes have a low risk.

“The crux of the matter is that this disease is really at least two distinct diseases,” said Hageman. “I believe recent clinical trials have failed because of a lack of this understanding. Sadly, companies may have had a drug that could have worked on patients with chromosome 1-directed AMD, but without excluding chromosome 10-directed AMD patients, they weren’t able to observe an effect.”

A Personalized Approach

From a practical standpoint, knowing AMD is at least two diseases makes a one-size-fits-all treatment impossible. Instead, Hageman has taken a personalized medicine approach to tailor treatment to each patient’s genetics. Using eye tissue from 350 donors representing seven genotype groups, the SCTM generated 9.2 billion points of data to deconstruct the complex molecular pathways involved in chromosome 1- and chromosome 10-directed AMD. The effort supported development of a new therapy designed to help people with the greatest genetic risk for chromosome 1 AMD—patients Hageman estimates represent a significant proportion of AMD patients in the U.S. alone.

The SCTM has partnered with newly funded startup Voyant Biotherapeutics to commercialize the new therapy, which will be delivered to the retina with the goal of slowing—even halting—disease progression. Pre-clinical testing exceeded expectations, and funding has been secured to move forward into clinical trials.

 

“I don’t think there’s anyone doing what Greg’s doing. There are people doing little individual elements. But there is no one else in the world with the same kind of vision and momentum, and team and resources.”

Tiarnan Keenan, Moran Adjunct Professor

In 2017, the FDA approved the first gene therapy for an inherited ocular disease. The SCTM treatment could be the next such therapy as physicians and researchers embrace personalized medicine.

“The dream for the future is to ultimately treat patients based solely on their genetics,” said Hageman. “If I am a patient, and I have one drusen but a 70 percent chance of developing AMD, I would want to be treated early. This is personalized medicine at its best. This is the world we’re going to live in.”

The SCTM will soon begin a rigorous new study aimed at fully understanding how AMD progresses in genetic subsets of patients. That’s where world-renowned clinician researchers and spouses Monika Fleckenstein, MD, and Steffen Schmitz-Valckenberg, MD, come in.

Monika Fleckenstein, MD
Monika Fleckenstein, MD

“Being involved in this is the chance of a lifetime. Greg is a pioneer in AMD research, and it’s a logical consequence that all of his research work from the past 30 years now ends in an interventional trial.”

Monika Fleckenstein, Moran Adjunct Professor

The DREAM1 Study

Fleckenstein is a longtime SCTM collaborator and will join Moran’s full-time faculty in 2019 as the former head of the University of Bonn Department of Ophthalmology Clinical Trial Center. She will oversee the DREAM1 study (named for Hageman’s dream to cure AMD and short for Drusen Endpoint Assessment Morphology Study in Chromosome 1-Directed AMD), which will determine exactly how homozygous chromosome 1-directed AMD progresses in patients and the appropriate stage in the disease to administer therapy.

Like Hageman, Fleckenstein believes treatment at an early disease stage is critical.

“We all fear that there is this point of no return where you simply cannot save the retina,” said Fleckenstein. “If you have a clinical trial that lasts for 12 months and the retina is already predetermined to die, treatment is not going to work. The timing of the therapy and the measures you choose to evaluate success need to fit together.”

The wide-reaching DREAM1 initiative, which will include centers across the U.S. and Europe, won’t stop at chromosome 1. The study will gather similar data to support a treatment in the works for homozygous chromosome 10 AMD patients and then move on to examine a host of other genetic combinations.

Armed with DREAM1 study data, Fleckenstein and Schmitz-Valckenberg will develop criteria for measuring changes in the retina and determine protocols used to evaluate the success of the chromosome 1-based therapy.

Steffen Schmitz-Valckenberg, MD
Steffen Schmitz-Valckenberg, MD

“Moran is the best place in the world to be at the moment for AMD research. Many people are interested in AMD research, and many things are going on. But we really want to do profound research, and I believe what Greg is doing here is very well thought out.”

Steffen Schmitz-Valckenberg, Moran Adjunct Professor

Finding the Right Measures

Internationally recognized for his ophthalmic imaging research as head of the Grading of Digital Fundus Examination (GRADE) Reading Center at the University of Bonn, Schmitz-Valckenberg will also join Moran as a full-time faculty member this year.

As a child, Schmitz-Valckenberg was drawn to photography as a hobby. Now he’s at the forefront of efforts to use a variety of imaging techniques to map the stages of retinal decline in AMD. He recently published imaging protocols for clinical studies in advanced AMD as part of an international panel.

Visual acuity is often used to evaluate success in ophthalmic clinical trials, but is a poor outcome measure for AMD. Imaging may show regions of atrophy in the retina where cells are dying, yet AMD patients will often have normal vision for some time before their sight slowly deteriorates. What’s more, rates of deterioration vary. Schmitz-Valckenberg will build a new reading center at Moran that will evaluate retinal images, measuring not only atrophy but also drusen and retinal sensitivity.

“The best case scenario is that you show statistics that the treatment is working against placebo, but you also have to demonstrate an effect for the patient—for example, that drusen regress or that patients are not developing atrophy,” he said.

As the therapy advances, institutions around the country and the world will be involved in clinical trials—all sending images to Moran’s reading center for a systematic, rigorous analysis.

The Power of a Dream and a Team

In the past year, Hageman has recruited several other top researchers to join the SCTM team in full- and part-time roles.

When asked what’s kept him going for three decades, first through highs and lows of federal funding and then through years of methodical research as some scientists criticized him for not immediately publishing his findings, Hageman’s answer is this: “One has to be stubborn, stick with dreams and surround themselves with talented individuals with similar thinking. It really takes a village to do the type of work we are engaged in, and we’ve built an incredible village to see this task
through.”

To get this far, Hageman says, it’s taken the support of more than 4,800 patients enrolled in an SCTM genetics study, thousands of organ donors who have left their eyes to science, generous philanthropists who have donated millions of dollars, and unique collaborations with private industry partners. Not to mention the leadership of Moran CEO Randall J Olson, MD, who has supported the SCTM’s unconventional approach to fast-track new therapies.

“Academia has to get to a place where they allow people to take this unique approach,” said Hageman. “If it hadn’t been for Randy Olson seeing that, no way would we have been able to do what we’ve done.”

SCTM research activities hold promise not only for AMD treatments, but also for numerous other diseases associated with the genetics of the complement system.

“The future will be taking the drugs we have designed for chromosome 1- and 10-directed AMD and using them to treat other systemic diseases,” he said with a smile. “But that won’t be my job. That we will save for the young folks.”

Photos of a normal retina, drusen, and advanced AMD. AMD involves deterioration of the macula, which is the small central area of the retina responsible for seeing fine detail. Patients with AMD face a gradual loss of their central vision. Since no other organism has AMD, it’s essential for researchers to work with donated human tissue and study subjects.

“You choose collaborators because of the sense of trust, shared values, shared sense of mission, and shared focus. What flows from that is the ability to get on with the job—so that there are great challenges that need to be sorted, that can be sorted, and the process of doing it is fun.”

Philip Luthert, Moran Adjunct Professor
New members of the SCTM team include, from left, Tiarnan Keenan, MD, PhD; Moussa Zouache, PhD; and Philip Luthert, MBBS, FRCP, FRCPath, FRCOphth.
New members of the SCTM team include, from left, Tiarnan Keenan, MD, PhD; Moussa Zouache, PhD; and Philip Luthert, MBBS, FRCP, FRCPath, FRCOphth.

A Growing Team

The SCTM recently recruited nine international experts to help bring the first AMD treatment based on a patient’s genetic makeup to clinical trials:

Catherine Bowes Rickman, PhD, adjunct professor; Duke University Eye Center, an expert on preclinical drug testing and modeling, and the pathobiology of AMD.

Eugene de Juan, MD, adjunct professor; University of California, San Francisco, a renowned retinal specialist, inventor, and entrepreneur focusing on ocular medical and surgical therapeutics, including
advances in drug delivery techniques for AMD.

Monika Fleckenstein, MD, adjunct professor; University of Bonn, Germany, an international authority on the design, conduct, and analysis of interventional clinical trials for retinal disease therapies.

Tiarnan Keenan, MD, PhD, adjunct professor; National Institutes of Health National Eye Institute, a specialist in the pathogenesis of AMD who worked with Hageman as a U.K./U.S. Fulbright scholar and will now assist with SCTM research.

Anat Loewenstein, MD, adjunct professor; Tel Aviv University, Israel, chair of the Department of Ophthalmology and vice dean of the Sackler Faculty of Medicine, an expert in early detection of AMD,
retinal toxicity of drugs, and vitreoretinal surgery.

Philip Luthert, MBBS, FRCP, FRCPath, FRCOphth, adjunct professor; former director of University College London Institute of Ophthalmology, a leading ophthalmic pathologist studying AMD at the tissue level who will analyze large-scale genetic, clinical, and other datasets.

“A lot of very good science has been done at the SCTM by some of the most talented scientists I have ever met. Everything is in place for me to now test theoretical work I’ve been doing against real-life data and help move the project forward by using tools from engineering, modeling, and biology to solve problems.”

Moussa Zouache, Moran Research Assistant Professor

Steffen Schmitz-Valckenberg, MD, adjunct professor; University of Bonn, Germany, an acclaimed expert in high-resolution retinal imaging who will inform clinical trial design and develop protocols for assessing patient data.

Larry A. Wheeler, PhD, research professor; University of Utah, a specialist in AMD drug discovery and development and former senior vice president of biological sciences at Allergan, which collaborated with Hageman’s team on a robust gene expression study.

Moussa Zouache, PhD, research assistant professor, University of Utah Department of Ophthalmology & Visual Sciences, an expert in mathematical modeling from France who will assess sets of histological, clinical and genomic data, screen drug data, and identify responders to treatment.

The group joins SCTM adjunct professors Karen Curtin, PhD, MStat; and Debra A. Schaumberg, OD, MPH, ScD. Clinical and research team leaders supporting the SCTM are Jill Hageman, RN; Burt Richards, PhD; Brandi Williams, PhD; and Lisa Nichols.

Timeline to Treatment

Eye Repository

1987

Gregory S. Hageman, PhD, begins collecting human eye donations to examine the biology of AMD. Today, his repository includes over 8,500 pairs, the largest in the world dedicated to the study of normal and diseased retinal tissue.

Donated eye tissue at the SCTM lab.
Donated eye tissue at the SCTM lab.

Landmark Finding

2000

Hageman discovers that abnormalities in the Complement Factor H (CFH) gene on chromosome 1, which regulates a part of the body’s immune system, are associated with an increased risk for, or protection from, developing AMD. He files numerous patent applications and publishes his work in 2005.

2006

The National Institutes of Health awards Hageman $23 million to study the role of CFH disease. The program includes colleagues from 12 national and international institutions.

2007

Hageman founds Optherion, Inc., which raises $45 million to develop therapies for AMD.

New Opportunity in Salt Lake City

2009

Hageman establishes Moran’s Center for Translational Medicine (CTM) to quickly and cost-effectively turn scientific discoveries into diagnostics and therapies for blinding eye conditions, with a focus on AMD.

Genetic Study

2010

The CTM begins recruiting participants for an ongoing genetic study of AMD. More than 4,800 people, with and without AMD or a family history of the disease, are enrolled so far. Study participants are screened and genotyped for future AMD treatment trials. The effort includes a partnership with the Utah Population Database, one of the world’s richest sources of genetic and other in-depth health information.

Two Distinct Diseases

2011

The CTM confirms AMD is at least two distinct diseases, each of which will likely require its own unique
course of treatment.

  • A cluster of genes on chromosome 1, which plays a critical role in the immune system, causes one form
    of AMD.
  • A pair of genes on chromosome 10, which control an important pathway in the back of the eye, causes a second biologically distinct form of AMD.
Chromosomes 1 and 10 account for more than 90 percent of the risk for developing AMD.

Biotechnology Partner

2012

Hageman and colleagues found Voyant Biotherapeutics, LLC, a biotechnology company partnering with Moran to capitalize the commercialization of scientific discoveries made within the CTM. Voyant mediates a partnership between the CTM and Allergan, Inc. to expedite the pace of development of novel AMD therapeutics.

Therapy Targets

2014

A massive CTM/Allergan-led gene expression study generates about 9.2 billion data points and sheds new light on therapeutic targets for gene-directed AMD.

Major Gifts

2016

The CTM is renamed the Sharon Eccles Steele Center for Translational Medicine (SCTM) in honor of Sharon Eccles Steele, who pledged $9 million to support its mission as part of a larger fundraising campaign supported by many generous donors.

From left, Tiarnan Keenan, MD, PhD; Moussa Zouache, PhD; Monika Fleckenstein, MD; Gregory S. Hageman, PhD; Steffen Schmitz-Valckenberg, MD; Philip Luthert, MBBS, FRCP, FRCPath, FRCOphth; and Randall J Olson, MD.
From left, Tiarnan Keenan, MD, PhD; Moussa Zouache, PhD; Monika Fleckenstein, MD; Gregory S. Hageman, PhD; Steffen Schmitz-Valckenberg, MD; Philip Luthert, MBBS, FRCP, FRCPath, FRCOphth; and Randall J Olson, MD.

Clinical Trial In Sight

2018-2019

The SCTM develops a new therapy for chromosome 1-directed AMD, and pre-clinical testing produces viable drug candidates. Moran and a health care investment firm commit approximately $50 million to fund clinical trials for the new therapy. The SCTM team continues to pursue a therapy for the chromosome 10 form of AMD.

2020

The SCTM and Voyant anticipate initiation of a phase 1 trial.

Speaking Engagements

2019

Hageman will speak at two upcoming conferences:

  • 12th International Conference on Complement Therapeutics, Rhodes, Greece 
"Complement-directed Age-related Macular Degeneration is a Distinct Subset of the Disease: Gene-directed Therapeutics and Patient Stratification Will be Prudent Strategies for Future Clinical Trials"
Gregory S. Hageman, Burt Richards, Chris Pappas, Robert Anstadt, Jin Liu, Brandi Williams, Nathan Seager, Larry Wheeler, Karen Curtin, and Jill Hageman

  • 7th International DOG-Symposium on AMD, Baden-Baden, Germany

 

vision research AMD patient care genetics personalized medicine