$14.6 million NIH Grant will build on macular degeneration findings

A five-year, $14.6 million grant from the National Eye Institute of the National Institutes of Health (NIH) will fund an international, multidisciplinary effort led by the University of Iowa to leverage two recent genetic discoveries into possible treatments for age-related macular degeneration (AMD). The grant was awarded Aug. 1.

Gregory Hageman, Ph.D., professor of ophthalmology and visual sciences at the University of Iowa Roy J. and Lucille A. Carver College of Medicine, will lead the multi-institutional effort.

AMD is the most frequent cause of irreversible blindness in developed countries. People with AMD lose the central part of their vision when the macula, a part of the retina, degenerates. No treatment currently exists for early stages of AMD, which affects nearly 50 million people worldwide. Treatment for advanced stages is very limited.

In the past year, the UI, Columbia University Medical Center and the National Cancer Institute (NCI), along with several other institutions, determined that two genes -- complement factor H and factor B -- account for nearly three out of four cases of AMD. Variations in these two genes somehow alter the function of a key pathway in the immune system, which researchers suspect leads to AMD. The factor H gene also is linked to similar eye problems associated with membranoproliferative glomerulonephritis type II (MPGN II), a rare kidney disease.

Now, the scientists will begin a series of investigations to learn more about the genes' role in the immune system, with the goal of developing diagnostic tools and treatments. The team will explore how the gene variations affect function of the factor H protein and explore the idea that replacing, augmenting or removing the malfunctioning protein can delay or even prevent the eye disease caused by AMD and MPGN II.

"For the first time, we have strong data on which to base the next phases of research into AMD. We're excited that the NIH grant will allow us to explore and advance our ideas related to the role of these genes in development of AMD," Hageman said.

"This research requires a multidisciplinary team capable of approaching this challenge from many different investigational angles. I'm enthusiastically looking forward to working with my co-investigators, all of who share the overall dream of ultimately developing therapies for AMD," he added.

The investigation includes efforts to determine whether other genes are associated with AMD and whether other inflammation-based diseases, such as Alzheimer's disease, are caused by dysfunction of the same, or a related, pathway. Additional aims involve studying the biology of the eye's complement system to determine whether proteins and markers, other than a vision test, can reveal vision decline due to AMD. Other efforts funded by the grant would involve drug design and development and clinical trials.

One of the international collaborators is Giuliana Silvestri, M.D., head of surgery and perioperative care in ophthalmology at Queen's University in Belfast, Ireland. "Silvestri's extensive clinical expertise in the diagnosis and management of AMD patients will be essential to the project, especially as it enters any translational, or treatment-related, phase," Hageman said.

The participation of patients and families in Iowa, Ireland and other sites will play a critical role in the research program. Silvestri, for example, already has identified many large families with AMD.

"The DNA resource is of particular value given that the Irish population is characterized by large families and stability," she said. "The addition of these families to this research program may provide additional insights into other genes implicated in AMD.

"This project has the potential to make significant inroads into real treatment benefits for AMD patients, which for a clinician at the bedside is very exciting. Secondly, from a personal viewpoint as a non-U.S. investigator, the opportunity to collaborate on such a project is a great honor," Silvestri added.

As part of the research, Brian Martin, Ph.D., UI assistant professor of microbiology, will lead efforts to clone and express the complement genes associated with AMD and to develop an animal model of the disease.

"It is very exciting to be working on a research project that might lead to an AMD treatment in the near future," Martin said.

In addition, Richard Smith, UI professor of otolaryngology and the Sterba Hearing Research Professor, will contribute to efforts to understand the links between MPGN II and AMD.

"The particular variation in the factor H protein that predisposes persons to developing AMD is found even more frequently in people with MPGN II, suggesting that intense, focused efforts on MPGN II will provide a unique opportunity to understand the cause and to develop treatments for both of these diseases," Smith said.

In addition to the UI, Columbia University Medical Center, the NCI, and Queen's University, other institutions involved in the NIH study include Washington University in St. Louis, University of California at Santa Barbara, University of California at Los Angeles, University College of London, the University of Helsinki in Finland, the University of Melbourne in Australia, the Shangdong Eye Institute and Beijing University, both in China, Centre de Neurochimie in Strasbourg, France, and Clinica Las Condes in Santiago, Chile.

"In the United States alone, nearly one-quarter of individuals age 70 and older show signs of AMD, a devastating eye disease that has a huge impact on individuals' lives and society as a whole," said Jean Robillard, M.D., dean of the UI Carver College of Medicine. "The NIH study led by Dr. Hageman has tremendous potential for translating important recent discoveries into patient care."

"It's wonderful for the University of Iowa to take the lead in advancing such a promising line of research," said Meredith Hay, Ph.D., UI vice president for research. "We are fortunate to have Dr. Hageman coordinating this AMD project. It reflects the innovative thinking and insightfulness that characterize our researchers and could bring real change to treatment options for people with this debilitating disease."

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These UI news releases provide additional information about the earlier genetic findings:
www.uiowa.edu/~ournews/2006/march/030606macular-degeneration.html
www.uiowa.edu/~ournews/2005/may/050205amd_study.html.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at www.uihealthcare.com.

STORY SOURCE: University of Iowa Health Science Relations, 5137 Westlawn, Iowa City, Iowa 52242-1178

MEDIA CONTACT: Becky Soglin, 319-335-6660, becky-soglin@uiowa.edu

PHOTOS/IMAGES:
G. Hageman: http://webeye.ophth.uiowa.edu/dept/BIOGRAPH/hagemapx.htm R. Smith: www.uihealthcare.com/depts/med/otolaryngology/faculty/smithrich.html B. Martin: www.medicine.uiowa.edu/microbiology/faculty/martin.htm


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