Improving Diagnosis and Treatment of Active Demyelinating Disease in Multiple Sclerosis by Targeting Myeloperoxidase

John W. Chen, M.D., Ph.D.

Harvard Medical School

Funded in June, 2007: $100000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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New MRI Imaging Agent May Improve Early Diagnosis and Treatment Monitoring in Multiple Sclerosis

This study in the animal model of multiple sclerosis (MS) will test the ability of a new MRI imaging agent to detect active clinical disease at the earliest stages and monitor changes produced by treatments.  The technique also may lead to the development of new treatment strategies.

MS is a progressive autoimmune disease of the brain and spinal cord. Errant inflammatory immune cells episodically destroy the myelin sheath that insulates nerve axons (communication cables). Conventional MRI imaging is used to non-invasively confirm a diagnosis of MS based on clinical symptoms, but currently is unable to definitively differentiate active inflammation from chronic underlying disease.  A newly developed MRI contrast agent, however, may detect the earliest signs of active inflammation.  This “smart” agent works by detecting myeloperoxidase (MPO), an enzyme released by inflammatory immune cells such as macrophages, and catalyzes chemical interactions that can kill cells.  The MPO-detecting contrast agent provides an intense and prolonged MRI signal that, the researchers hypothesize, will enable detection of active inflammatory demyelinating lesions. They will validate the agent’s accuracy through biochemical and tissue studies in the imaged animals. They also will test the effects of immunosuppressive therapies and MPO inhibitors to see how well the imaging technique assesses treatment efficacy.

Significance:  This new imaging technique may lead to improved means to diagnose MS, and to test the effectiveness of various types of treatment.

ABSTRACT

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Improving Diagnosis and Treatment of Active Demyelinating Disease in Multiple Sclerosis by Targeting Myeloperoxidase

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.

INVESTIGATOR BIOGRAPHIES

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John W. Chen, M.D., Ph.D.

Dr. Chen’s primary research interest is on discovering and developing novel multi-modality contrast agents to report molecular events in neurological diseases, in particular neurovascular and neurodegenerative diseases. His laboratory is currently focusing on developing and validating MR and nuclear contrast agents targeting myeloperoxidase, an enzyme secreted by activated macrophages and neutrophils in a variety of inflammatory diseases, including vulnerable plaques in atherosclerosis, multiple sclerosis, certain cancers, Alzheimer’s disease, and stroke.