December 5, 2018
Project combines highly sensitive biomarker discovery with human stem cell technology to develop a much needed blood diagnostic assay for Parkinson’s disease
By Benjamin Boettner
(BOSTON) — Today, the Chan Zuckerberg Initiative announced a project in its new Neurodegeneration Challenge Network in which Wyss Institute Core Faculty members David Walt, Ph.D., and George Church, Ph.D., together with Alice Chen-Plotkin, M.D., a clinical expert in neurodegenerative diseases at the University of Pennsylvania aim to develop tools to better diagnose and monitor the progression of Parkinson’s disease in simple blood samples.
To date, treatments for Parkinson’s disease merely alleviate the motor symptoms in patients but do not slow down the progression of the disease. To improve therapeutic outcomes researchers must be able to track the progression of molecular changes in response to different medications. The funded project leverages the unique expertise from the three research groups with their laboratories at Harvard’s Wyss Institute for Biologically Inspired Engineering, the Brigham and Women’s Hospital, Harvard Medical School, and the University of Pennsylvania to address this urgent diagnostic need.
“This collaborative project aims to identify biomarkers released from brain neurons that can serve as signatures of early stage Parkinson’s and provide us with clues about the disease’s neuropathology. These biomarkers, if detectible in blood, may also be used as a non-invasive diagnostic test to systematically monitor drug candidates in clinical trials that could potentially slow or stop disease progression,” said David Walt, who also is the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard Medical School and Professor of Pathology at Brigham and Women’s Hospital. “We are working towards such a test with the combined forces of our teams.”
With his group at the Wyss Institute and the Brigham and Women’s Hospital, Walt has developed ultrasensitive assays for a panel of biomarkers based on modifications to Parkinson disease-relevant proteins after they are synthesized (translated) in neuronal cells of affected regions of the brain. While Walt’s team can detect these biomarkers with a new technology called Single Molecule Arrays (Simoa) that is 100 to 1000 times more sensitive than conventional assays and can measure these protein modifications in cerebrospinal fluid from patients with Parkinson’s disease, their method is still not sensitive enough to be used with much more easily obtainable blood samples.
To be able to apply this assay to blood samples, the collaborating groups have set their eyes on exosomes, small vesicles that brain cells – like all other cells in the body – secrete into their environment, and that also contain some of the cells’ contents. When exosomes pass from brain fluids through the blood-brain-barrier into the normal blood circulation, they, in theory, should contain the molecular signatures of disease-affected brain tissue that could be detected using the Walt group’s biomarker panel for Parkinson’s disease. However, the main challenge is that brain-derived exosomes represent only a tiny fraction of the total number of exosomes present in blood. Consequently, brain-derived exosomes must be first efficiently isolated before they can be analyzed.