Pathfinder: An experimental medicine study of the 18 kD translocator protein as a novel neuroimmunodulatory target for multiple sclerosis

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Multiple sclerosis (MS) involves inflammation in the brain caused by lymphocytes that that circulate in the blood, by macrophages derived from another set of blood cells and by microglia, which are the brain's own resident inflammatory cells. Although treatments developed to date have focused on better controlling lymphocyte activity, microglia (and macrophages, which share some key features of microglia) also play a major role in the inflammation associated with relapses. They also may be important in driving the neurodegeneration associated with progressive forms of the disease. Our group has discovered, for example, that disability in secondary progressive MS is greater in people with higher levels of microglial activation in the brain. However, activated microglia are not directly modulated by current approved medicines for MS. The "18kD Translator Protein" or "TSPO" is a natural molecule richly expressed in microglia and macrophages. Studies by many scientists using cells in a dish or animal models of diseases suggest that chemicals (e.g., some related to common anti-anxiety drugs like valium) binding to TSPO reduce inflammation. This suggests that TSPO may provide a new way of modulating inflammation associated with MS and, as molecules developed to interact with TSPO all can penetrate the brain, have a unique action on microglia. This possibility has never been tested in human studies.To address this, we are proposing a comprehensive series of experiments in humans and with human cells or tissue that are intended to evaluate TSPO as a novel immune modulatory target for treatment of people with MS. We are focusing on secondary progressive MS because it is a serious, progressive form of the disease associated with high levels of brain microglial activation that cannot be well treated with current approved medicines. Our study will involve studies of brain tissue (donated to the MS Society Brain Bank by people with MS) to see whether TSPO is increased in microglia that are producing the kinds of chemical signals that damage nerve cells and myelin. We will study the inflammatory responses of human microglia grown in a dish when they are treated with molecules that modulate TSPO functions. Finally, under very carefully controlled conditions, we will administer the safe TSPO binding molecule XBD173 to healthy volunteers and to people with MS daily for a week to understand whether immune responses really can be changed with administration of this kind of molecule. Multiple measures of inflammation in the blood and in the brain will be used. Relatively new magnetic resonance imaging (MRI) and positron emission tomography (PET) brain scanning methods will be further validated for this application and then used as an additional tool in the healthy volunteers and people with MS to provide information more directly about the effects on brain inflammation.Our interdisciplinary clinical study will bring together a broad range of experts in drug development for MS, neuroimmunology and neuroimaging. It will provide a first test of the hypothesis that a TSPO binding molecule can modulate the inflammatory responses of microglia in humans, help us to discover how to monitor any effects that such molecules might be having and begin to tell us how they work. We do not believe that XBD173 itself can be used as a treatment, but many other molecules have been developed that should work in a similar way. If our study is successful, we intend to select and further develop one of these other molecules for use as a potential combination treatment with more traditional MS drugs. Together, a molecule modulating microglia and one of the currently approved disease modifying drugs that has a major effect on lymphocytes could provide a more powerful way of treating not just relapses, but also the progressive forms of MS.