PHILADELPHIA –Researchers at the University of Pennsylvania School of Medicine have created the first animal model of age-related macular degeneration (AMD) caused by a mutation known to produce disease in people, an important first step in developing treatments. The study appears in the October issue of Human Molecular Genetics.

Drusen

Drusen (extracellular deposits of protein and lipids that accumulate and can cause blindness) in macular degeneration.

A. Drawing of eye showing location of macula at the center of the retina.B. Photograph of the macula from a patient with drusen. C. Histologic section of retina showing drusen between the retinal pigment epithelium

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Age-related macular degeneration is the most common cause of vision loss in elderly people, affecting more than 10 million people in the U.S. and about 50 million world-wide. Although it is a common and debilitating condition, prevention and treatment options are limited because AMD is a difficult condition to study.

“To better develop treatments for preventing the progression of AMD, we need to understand the real biochemical details of how AMD occurs,” says lead author Eric A. Pierce, MD, PhD, Associate Professor of Ophthalmology at Penn’s K.M Kirby Center for Molecular Ophthalmology. “To do that, we need a model, and now we have one.”

AMD is a difficult condition to investigate because it develops late in life - patients typically show symptoms of AMD after 60, and the only samples researchers could use for study were from people who died while they had the early stages of AMD, and at that point, the tissue is not useful to study the condition’s progression.

AMD is caused by the development of deposits between the retinal pigment epithelium and its basement membrane, called Bruch’s membrane. The material starts as basal deposits and becomes drusen, extracellular deposits of protein and lipids that accumulate and can cause blindness. In order to prevent the basal deposits from forming, researchers need to understand the mechanisms that cause them to form in the first place.

“By making this particular mutant mouse, we’ve made a model of early macular degeneration that’s caused by a mutation we know produces macular degeneration in people,” says Pierce. “We think it’s going to be a good model to study the pathogenesis of basal deposits.”

Some forms of macular degeneration are inherited, and one type is thought to be caused by a mutation in the Efemp1 gene. Pierce and colleagues created a mouse model of this inherited disorder by introducing the disease-causing mutation into the Efemp1 gene of mice. The resulting Efemp1-mutant mice develop the same basal deposits as people with AMD.

Pierce and colleagues plan to use the Efemp1-mutant mice to study how basal deposits form and what they are made of. The mice can also be used to test potential treatments to prevent basal deposit formation.

In addition to Pierce, Li Fu and Donita Garland of Penn; Zhenglin Yang, Erik Pearson and Kang Zhang of the University of Utah Health Sciences Center; Dhananjay Shukla and Anand Rajendran of the Aravind Eye Hospital & Postgraduate Institute of Ophthalmology; and Edwin M. Stone of the Howard Hughes Medical Institute are co-authors.

The Rosanne Silbermann Foundation, Research to Prevent Blindness, the Foundation Fighting Blindness, the F.M. Kirby Foundation, the Ruth and Milton Steinbach Fund, Ronald McDonald House Charities, the Macular Vision Research Foundation, the Howard Hughes Medical Institute and the National Eye Institute provided funding for this research.

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

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