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2017 Grants - Fiorito
Drug Development of a Novel PDE5 Inhibitor for Alzheimer’s Disease
Jole Fiorito, Ph.D.
Columbia University Medical Center
New York, New York
2017 Alzheimer’s Association Research Fellowship (AARF)
Can a novel compound help preserve nerve cell function and prevent memory loss in Alzheimer’s disease?
Nerve cells communicate through specialized structures called synapses that connect one nerve cell to another. Cellular communication is necessary to support memory and other cognitive functions. In Alzheimer’s disease, synapses become damaged which may contribute to impaired nerve cell communication and cognitive decline. Recent studies by Jole Fiorito, Ph.D. and others have found that inhibiting a molecule called phosphodiesterase type 5 (PDE5) can help prevent synaptic damage and restore memory function in Alzheimer’s-like mice. Drugs that are PDE5 inhibitors (PDE5Is) are currently available to treat certain conditions in humans, but they are not optimized for the long-term treatment of brain disorders such as Alzheimer’s.
Dr. Fiorito has recently discovered a novel PDE5I that can effectively cross from the blood into the brain in Alzheimer’s-like mice and reduce synapse damage. However, when tested in human liver cells, the drug is broken down (metabolized) too quickly indicating it may not stay in the body long enough to have effects. For their current studies, Dr. Fiorito and team will develop chemical modifications of the candidate PDE5I to help prevent it from being too quickly metabolized in the liver. They also plan to optimize the structure of the candidate PDE5I to increase its ability to enter the brain and ensure it selectively targets pathways involved in nerve cell synaptic function. They will test their novel PDE5I in Alzheimer’s-like mice to evaluate its safety when given over long periods of time, and determine if it can help preserve synapses and improve memory function.
These studies provide the first important steps in the discovery and development of a novel drug molecule that may prevent or reduce brain changes associated with Alzheimer’s disease. If successful, the results of this effort could lay the foundation for future human clinical trials to determine if PDE5Is are a therapeutic avenue for slowing or stopping the progression of Alzheimer’s disease.