Posted January 15, 2013
Drs. Wang and Miller, Case Western Reserve University
The Multiple Sclerosis Research Program (MSRP) Synergistic Idea Award funded Drs Wang and Miller from Case Western Reserve University to work together to use a newly developed myelin-imaging tool to discover novel therapeutics for multiple sclerosis (MS). The combination of novel myelin-imaging technique in Dr. Yanming Wang's laboratory with the biological understanding of oligodendrocyte development and model systems of demyelinating diseases in Dr. Robert Miller's laboratory provide a unique combination of expertise that is poised to initiate a series of pre-clinical therapeutic characterizations. Neither investigator alone could undertake the studies outlined in the proposal, which require integration of highly sophisticated radiochemistry and imaging protocols with state of the art biologic understanding of demyelination and remyelination.
An important goal of this project is to identify the most effective therapeutic agents that are suitable for clinical studies in human patients. In order to accurately identify lead agents suitable for human studies, in vivo assessment of myelin changes in central nervous system (CNS) models of MS must be developed for drug screening. For drug discovery and development in myelin repair therapy, one major challenge has been assessing and quantifying changes in myelin content in vivo. To date, magnetic resonance imaging (MRI) has been the primary tool for diagnosing and monitoring the demyelinating conditions in MS. Unfortunately, MRI is largely a non-specific measure of the overall changes in macroscopic tissue injury that ranges from edema, inflammation to demyelination and axonal loss and does not specifically reflect myelin changes. It is thus essential to develop a direct measure that will effectively correlate clinical outcomes with changes in myelin contents. For this reason, the researchers have developed a series of myelin imaging agents that can be readily used as radiotracers for positron emission tomography (PET), an in vivo imaging technique that is widely used in the clinic to monitor brain functions at the molecular level. The new myelin-imaging agents readily enter the brain and selectively localize in different brain regions in proportion to the extent of myelination. The major advance is utilizing the new myelin-imaging technique to quantify local levels of myelination which will facilitate the development of therapeutics that are directly focused at myelin repair. All current imaging approaches do not directly assay the levels of myelin in particular CNS regions and are therefore subject to substantial levels of interpretation. Once validated, it can be used as a powerful tool in screening of drug candidates and identify most promising therapies for clinical trials.
The new image-guided approaches outlined in this project will provide physicians and researchers with the capability to image endogenous myelin and quantify demyelination and remyelination with a high degree of spatial and temporal resolution, which will be critical for the development of novel therapeutics aimed at staple functional recovery in patients with MS and related acquired demyelinating diseases.