Multiple sclerosis (MS) is the leading cause of neurological disability in young adults. Early diagnosis with prompt treatment has been found to delay relapse and neuronal loss from inflammation. Imaging with activatable, “smart” agents targeting key enzymes in MS will improve the specificity and sensitivity of conventional imaging modalities such as magnetic resonance imaging (MRI), which has played an important role in the MS diagnosis, monitoring, and drug development.
Currently, a lesion that enhances with the conventional MRI contrast agent is thought to indicate "active" disease. However, this enhancement is nonspecific and reflects breakdown of the blood-brain barrier (BBB) rather than active inflammation and demyelination, and the two processes may not always correspond. MS lesions at all stages demonstrate some BBB breakdown with variable enhancement, and lesions can remain enhanced 1 to 13 weeks after the onset of clinical symptoms when imaged with conventional gadolinium. It has also been found that current conventional imaging underreports active MS lesions. Therefore, a better method is needed to image active disease to allow earlier diagnosis and treatment.
MS plaques result from an immune-mediated inflammatory response induced by certain inflammatory white blood cells. Myeloperoxidase (MPO), an enzyme secreted by inflammatory white blood cells, is found in active MS plaques. Individuals with different MPO genes also have different susceptibility to MS. We have recently developed the first small molecule enzyme-activatable sensor that works in vivo and highly sensitive to MPO activity. Because of the increased sensitivity and specificity from MPO activation, we hypothesize that active lesions at an earlier stage could be detected by this MPO-activatable sensor that would otherwise be missed by current imaging methods, and may be differentiated from lesions that are not truly active.
We will use this new MR imaging agent to image actively demyelinating, inflammatory MS plaques. In vivo imaging at the acute and chronic phases of an animal model of MS, experimental autoimmune encephalomyelitis, will be performed and correlated with biochemical assays and immunohistochemical analysis to evaluate and understand the roles immune cells lsuch as microphage/microglia and MPO play in the plaque development. We will also exploit both immunosuppressive therapy and MPO inhibitors to assess current and potential new treatment for MS. We believe that this technology, if proved to work as anticipated, will lead to better lesion characterization with earlier, more specific, noninvasive diagnosis of preclinical disease and treatment monitoring in therapy and drug trials.