Objective/Rationale:
Techniques for measuring in humans the activity of brain chemical pathways that are fundamentally involved in the initiation, progression or reversal of Parkinson’s disease would be of great value. Accordingly, our primary objective is to provide proof-of-concept that cerebrospinal fluid (CSF)-based biomarkers measuring microtubule-mediated transport of cargo molecules in neurons are altered in people with Parkinson’s disease.
Project Description:
New monitoring techniques that provide insight into the underlying pathophysiology of PD, disease progression and treatment response would represent a major advance in the area of neuro-restorative drug development. We have developed a novel stable isotope/mass spectrometric assay to measure impaired neuronal transport of key molecules in vivo in humans, prior to and during neuronal degeneration. The goal of this project is to develop and optimize the heavy water-mass spectrometric method for measuring neuronal transport and secretion of cargo molecules via the key microtubule system. We will enroll Parkinsonian and age-matched control subjects to test this assay as a real-time metric for monitoring disease progression and treatment response in Parkinson’s disease.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Measurement of impaired microtubule-mediated transport of key molecules by neurons in people with Parkinson’s disease might be useful in several ways. The natural history/pathogenesis of the disease may be revealed, thereby suggesting optimal points for intervention. Disease subtypes may be identified, allowing individualization or stratification of therapy. Testing and advancement of drug candidates in a much more cost-efficient manner may also be enabled, by allowing rapid proof-of-therapeutic concept Phase I or II clinical studies. This type of biomarker can be used for rapid assessment of disease progression by objective criteria other than clinical evaluation and can provide a pathophysiologic basis for monitoring treatment response.
Anticipated Outcome:
The anticipated outcome of the portion of these studies will be to determine whether CSF biomarkers of microtubule-dependent neuronal transport are altered in patients with Parkinson’s disease. Based on what we learn from this initial human proof-of-concept study, we anticipate broadening the application of CSF biomarkers of microtubule-dependent transport to large-scale Parkinson’s disease clinical studies and, ultimately, in simplified form, to patient management.
Progress Report
Parkinson’s shares with other neurodegenerative diseases altered microtubule function and neuronal transport deficits which can be detected and quantified in cerebrospinal fluid (CSF) of humans using isotopic labeling of transported cargo proteins. With KineMed’s innovative labeling method, humans drink heavy water, a safe, non-radioactive isotope of water. This heavy water diffuses throughout the body and becomes a building block for proteins in the brain that are newly synthesized during the period of labeling. By then isolating these labeled proteins from small samples of CSF and using an ultra-sensitive mass spectroscopic analysis, abnormal neuronal transport can be detected. These abnormalities can be measured precisely and rapidly, over periods of days to weeks, this approach is symmetrical in both animals and humans, making this method truly translational.
Currently there is a lack of effective therapies to treat neurodegenerative diseases. One of the main impediments to bringing forward new treatments has been the inability to translate insights in animals to humans, as a result, pharmaceutical and biotechnology companies have had to “drive blind” in translating animal results to humans, making it extremely difficult to demonstrate drug efficacy in early clinical development. The ability to measure dynamic processes occurring in the brain by analyzing CSF is the key that makes this method a powerful translational approach for developing novel therapies and can facilitate clinical trials for better treatments that modify the progression of Parkinson’s disease.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.