(PHILADELPHIA) – Researchers in the Perelman School of Medicine at the University of Pennsylvania will lead a multi-institutional effort in pursuit of developing a critical tool for imaging the brains of patients with Parkinson’s and other neurodegenerative diseases. The Center Without Walls — a collaboration between Penn Medicine, Washington University-St. Louis, the University of Pittsburgh, the University of California-San Francisco, and Yale University — has received a five-year $20 million grant from the National Institute of Neurological Disorders and Stroke (NINDS) to pursue this work.
“The NINDS set an incredibly ambitious goal that required an equally ambitious project,” said the Center’s principal investigator Robert H. Mach, PhD, the Britton Chance Professor of Radiology at Penn Medicine. “At the end of five years, we hope to have a radioactive tracer that will be able to detect Parkinson’s early on and provide detailed information about the disease’s progression, which is critical for discovering and testing new treatments.”
Parkinson’s disease, a progressive nervous system disorder, affects 10 million people worldwide and 500,000 in the United States. There is no single test available to diagnose the disease, and it can go undetected or misdiagnosed until its symptoms — tremors, changes in speech, and balance issues — become severe. The drug Levodopa, which was approved by the U.S. Food and Drug Administration for the treatment of Parkinson’s over 50 years ago and remains the gold standard of treatment, can become less effective as the disease progresses and is often accompanied by severe side effects.
Identifying a Parkinson’s imaging biomarker, or indicator of the disease process, would be a critical step for detecting the disease early, before irreversible damage to the brain occurs. Not only could a biomarker aid in early diagnosis, but it could allow researchers to speed clinical trials of new therapies, according to study co-investigator Andrew Siderowf, MD, MSCE, the Hurtig-Stern Professor of Neurology at Penn.
“Currently, when testing new drugs for Parkinson’s, assessing the patient’s clinical symptoms is the only way to measure whether or not the treatment is working, but clinical features evolve very gradually,” Siderowf said. “Having an imaging biomarker that is sensitive to changes in a Parkinson’s pathology could greatly accelerate drug development.”
A positron emission tomography (PET) scan is an imaging test that uses a radioactive drug (tracer) that binds to certain proteins or sugars, in order to show areas of the body that have higher levels of chemical activity, indicating disease. It was just under a decade ago that researchers first identified a radiotracer that could be used to detect the presence of amyloid protein plaques in the brain, which are a hallmark of Alzheimer’s disease. Though the search for a successful Alzheimer’s drug remains elusive, PET scans have revolutionized how the disease is diagnosed and monitored.
Now, Mach and his team at the Center Without Walls are pursuing a similar outcome for Parkinson’s and a handful of other diseases that are characterized as “proteinopathies,” which occur when certain proteins “misfold” and structurally abnormal. With this funding, the researchers plan to develop two different radiotracers: one that will bind to a protein in the brain known as alpha-synuclein for the imaging of Parkinson’s and multiple system atrophy, and the other that will bind to the protein 4R tau for imaging frontotemporal degeneration and progressive supranuclear palsy.
Identifying compounds that are able bind to the proteins alpha-synuclein and 4R tau is akin to “finding a needle in a haystack,” Mach said. To accomplish this undertaking, a research group within the Center Without Walls — led by E. James Petersson, PhD, an associate professor of Chemistry — will use a technology that can computationally screen for molecules, synthesize them, and interpret binding data based on crosslinking.
“Finding a needle in a haystack is much easier when you have a machine made to find needles,” Siderowf said.
The research team will also draw from the expertise of John Q. Trojanowski, MD, PhD, the William Maul Measey-Truman G. Schnabel, Jr. Professor of Geriatric Medicine and Gerontology in Pathology and Laboratory Medicine, and Virginia Man-Yee Lee, PhD, MBA, the John H. Ware 3rd Endowed Professor in Alzheimer’s Research. Trojanowski and Lee are also co-investigators on a separate project, funded recently by an $18 million NIH grant, to study the mechanisms of and connections between Alzheimer’s disease, dementia and Parkinson’s.
Mach says that a successful outcome from the Center Without Walls could not only change the course of Parkinson’s disease research, but could have a much wider impact.
“That would be a true paradigm shift in the way we develop molecular imaging probes to study neurological disease,” he said.
The Center Without Walls is funded by the National Institutes of Health (U19NS110456). Other Penn investigators include: David Mankoff, Ilya Nasrallah, Kelvin Luk, Vera Moiseenkova-Bell, Hsiaoju Lee, Robert Doot, Erin Schubert, Catherine Hou and Chia-Ju Hsieh.
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