Five-year NEI grant will be used to scan FDA-approved drugs for candidates.

Scientists at Case Western Reserve University have been awarded a five-year $10.1 million grant from the National Eye Institute (NEI) to research and develop new treatments for diseases of the retina. The investigators will screen FDA-approved drugs for their potential to treat eye diseases affecting the retina.

The NEI award will fund the work of scientists in the departments of pharmacology, ophthalmology, and biomedical engineering at the Case Western Reserve University’s School of Medicine. They will work with the Cincinnati Drug Discovery Center, the Retinal Therapeutics Study Group, the University of Pennsylvania, and Washington University.

The research builds upon work in laboratory of Krzysztof Palczewski, Ph.D., chair of the department of pharmacology and principal investigator of the NEI-funded research. His group 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. In older patients and those with age-related macular degeneration (AMD) and Stargardt-like diseases, however, one of the critical biochemical reactions in the series that recycles vitamin A is slowed. This allows a toxic byproduct that results from 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 researchers explain.

Dr. Palczewski’s group is 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. Potential therapies will be tested in basic research models of diseases like AMD, Stargardt disease, and retinitis pigmentosa. A noninvasive 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.

“Current treatments for AMD focus on management of the late stages of the disease,” says Jonathan H. Lass, M.D., 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. “These studies could result in treatments at the earlier stages and save more vision as a result.”

The NIH-funded research also includes evaluating existing FDA-approved drugs as potential lead compounds for retinal diseases. Researchers will likewise assess the ability of potential compounds to penetrate and remain in the eye without negatively affecting vision. They will also explore and develop new drug delivery systems to achieve and maintain therapeutic drug concentrations in the eye.

Dr. Palczewski and his team have already examined 24 FDA-approved drugs, from antibiotics to drugs fighting cancer and infectious diseases, in a mouse model of Stargardt disease for their ability to attack the buildup of harmful toxins in the retina. At least 16 of the drugs tested have already demonstrated the potential to limit the progression of retinal diseases, the scientists report. The resulting data provided the basis for funding the $10 million NIH grant request.

“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,” remarks Jonathan H. Lass, M.D., 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.”

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