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Case Western Reserve receives $10M to study retinal disease, develop new treatments
Date:12/28/2010

The Departments of Pharmacology and Ophthalmology and Visual Sciences at Case Western Reserve University School of Medicine have been awarded a $10.1 million grant from the National Eye Institute (NEI) to research and develop new treatments for diseases of the retina, a leading cause of blindness.

"The grant strongly positions the School of Medicine and collaborating organizations to play a significant role in advancing the treatment of retinal diseases in order to restore quality of life to countless patients," said Jonathan H. Lass, MD, professor and chair of the Department of Ophthalmology and Visual Sciences at Case Western Reserve School of Medicine and director of the University Hospitals Eye Institute. "It is the largest grant of its kind ever awarded to the university by the National Eye Institute, a tremendous achievement."

The NEI, part of the National Institutes of Health (NIH), will award the grant over five years, funding the work of researchers in the Departments of Pharmacology, Ophthalmology, and Biomedical Engineering at the School of Medicine who are working in collaboration with the Retinal Therapeutics Study Group. This interdisciplinary consortium of investigators is screening FDA-approved drugs for their potential application to the treatment of eye diseases affecting the retina.

The combined group, which also includes researchers from the Cincinnati Drug Discovery Center, the University of Pennsylvania and Washington University, aims to accelerate the rate at which basic science discoveries are used to develop new therapies for complex retinal disorders and diseases.

Conditions affecting the retina, the tissue in back of the eye responsible for vision, are a primary cause of blindness in adults in the United States. Such diseases include age-related macular degeneration (AMD), the main cause of blindness in adults over the age of 55. More than 1.3 million people in the U.S. are legally blind and 8 to 10 million aging individuals show signs of developing AMD, an incurable eye disease characterized by damage to the retina and the loss of central daylight vision.

"The research being funded by the NIH is critical to availing patients of new, more effective treatments, particularly for diseases like AMD, for which there is currently no cure," says Krzysztof Palczewski, PhD, John H. Hord Professor, chair of the Department of Pharmacology, and principal investigator and director of the research funded by the new NEI grant. "Our goal is to develop new drugs based on the screening of FDA-approved drugs to evaluate their effectiveness in treating retinal diseases."

Researchers will employ a range of scientific expertise and state-of-the-art physiological, chemical and analytical imaging technologies to test potential retinal disease therapies in basic research models. A non-invasive imaging technology developed at Case Western Reserve by Dr. Palczewski's research group will facilitate monitoring of the retina to detect molecular changes, defects, or harmful toxins in the retina.

FDA-approved drugs will be screened for their potential application in research models engineered to mimic conditions such as AMD, Stargardt's disease (a form of inherited juvenile macular degeneration) and retinitis pigmentosa (a group of inherited retinal disorders characterized by progressive peripheral vision loss). The drug-screening process is designed to accelerate the process of drug development before clinical testing in humans.

Dr. Palczewski is working with researcher Akiko Maeda, MD, PhD, senior instructor in the Departments of Ophthalmology and Pharmacology; and Zheng-Rong Lu, PhD, professor of biomedical engineering; to hone in on existing drugs with chemical properties and initial research results that suggest they may provide a basis for developing new drugs for treating retinal diseases like AMD.

The research builds upon previous work in Dr. Palczewski's laboratory which identified mechanisms in the eye responsible for metabolizing vitamin A, an essential step in triggering the nerve signals sent to the brain to enable vision. Researchers determined that in healthy patients, this visual cycle operates rapidly. However, in older patients and those with AMD and Stargardt-like diseases, one of the critical biochemical reactions in the series that recycle vitamin A is slowed. This allows a toxic byproduct produced by the breakdown of vitamin A to accumulate, which damages the retina over time, probably contributing to the development of AMD and/or impairing vision.

The combined teams in Ophthalmology and Pharmacology are now looking for drugs that can target the mechanism that captures toxic vitamin A metabolites, to neutralize and counter the build-up of any visual cycle toxic byproduct, as a means of preventing or controlling retinal diseases. "Current treatments for AMD focus on management of the late stages of the disease. These studies could result in treatments at the earlier stages and save more vision as a result" says Dr. Lass.

In addition to testing existing FDA-approved drugs for their ability to reduce toxic substances within the retina, priorities for the NIH-funded research also include evaluating existing FDA-approved drugs as potential lead compounds for retinal diseases because these drugs have already been proven safe and effective in basic research and clinical studies for other indications. Researchers will likewise assess the ability of potential compounds to penetrate and remain in the eye without negatively affecting vision and they will explore and develop new drug delivery systems to achieve and maintain therapeutic drug concentrations in the eye.

"We have an idea as to what drugs could be most effective for our purposes," said Dr. Maeda, who relocated from Japan to the United States to work with Dr. Palczewski. She is the study's co-principal investigator and a group leader who is responsible for basic research models. "During my clinical practice in ophthalmology, I was very frustrated with the lack of treatment options for many patients with retinal degenerative diseases, and I became determined to dedicate myself to developing new treatments for these patients through basic science research. I am very excited to develop our ideas for treating currently incurable retinal diseases."

Dr. Palczewski and his team have already examined 24 FDA-approved drugs, from antibiotics to drugs fighting cancer and infectious diseases, for their ability to attack the buildup of harmful toxins in the retina. These studies were done with mice that were genetically engineered to mimic Stargardt's disease. At least 16 of the drugs tested have already demonstrated the potential to limit the progression of retinal diseases. The resulting data provided the basis for funding the $10 million NIH grant request.


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Contact: Jessica Studeny
jessica.studeny@case.edu
216-368-4692
Case Western Reserve University
Source:Eurekalert

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