From therapeutic mechanisms to unraveling the pathophysiology of MS

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Multiple Sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS). The etiology of MS remains unclear, but the disease develops in genetically susceptible individuals exposed to environmental triggers. The long-favored hypothesis in MS implicates autoreactive T and B cells generated in the periphery that access the CNS, where they induce injury of previously normal neural tissues. However, in contrast to the animal model experimental autoimmune encephalomyelitis (EAE), neither the target(s) of the immune response nor the cells responsible for CNS damage have been unequivocally defined in MS. Furthermore, the failure of some MS disease modifying treatments (DMTs) that target processes underlying the development of CNS tissue destruction in EAE (e.g. IFN-g, TNF-a inhibitors) indicates that different mechanisms may cause the development of disability in MS versus EAE. Therefore, there is a need to identify pathophysiological mechanisms that are specific for MS, but may not be predicted from EAE models. Therapeutic trials represent an opportunity to investigate how specific perturbations of the biological system affect MS disease process. The goal of this project is to carefully study the biological perturbations induced by the application of novel therapeutic agents in Phase I/II clinical trials in MS, to define mechanisms of CNS tissue injury, but also those that underlie beneficial immunoregulation and immune-mediated neuroprotection. By correlating changes measured in the biological system with structural changes of CNS destruction (measured by neuroimaging), and with novel, more sensitive clinical and functional outcomes, we can understand which biological processes are beneficial and which are harmful in the MS pathogenesis. Additionally, understanding which effects of applied therapies underlie their therapeutic benefit will allow us to define biomarkers that are indicative, and ideally also predictive of the full therapeutic response. Finally, we also believe that analogously to cardiovascular, infectious diseases or oncology, successful treatment of fully evolved CNS disorder will require rational, patient-specific combination treatments that target all pathogenic mechanism responsible for his/her disease expression. This project is an extension of the: Comprehensive multimodal analysis of patients with neuroimmunological diseases project, in that it tests hypotheses derived from this project in interventional, investigator-initiated clinical trials. In 2017 we opened adaptive, platform Phase II clinical trial called TRAP-MS: Targeting Residual Activity by Precision, biomarker-guided combination therapies of Multiple Sclerosis (protocol 17-N-0083; clinicaltrials.gov identifier NCT03109288). TRAP-MS trial tests hypotheses derived from the knowledge we acquired in the past 6 years under project: Comprehensive multimodal analysis of patients with neuroimmunological diseases about residual MS activity when patients are treated with current FDA-approved DMTs and about pathogenic processes associated with disease progression and disease severity in MS. Specifically TRAP-MS trial tests following hypotheses: 1. Large proportion of MS patients treated with FDA-approved DMTs retain measurable inflammation that is compartmentalized to the CNS tissue and consists of terminally-differentiated (and therefore largely non-proliferating) immune cells. This inflammation contributes to CNS tissue destruction and may be limited by hydroxychloroquine, which limits antigen-processing/presentation and perforin/granzymes-mediated cytotoxicity. 2. Chronic intrathecal inflammation leads to activation and reprogramming of innate immunity cells, especially myeloid lineage, which contributes to CNS tissue destruction and accumulation of disability. This inappropriate activation of myeloid lineage (microglia, macrophages and myeloid dendritic cells) may be inhibited by pioglitazone. We have shown in-vitro that pioglitazone also corrects functional defect in myelin phagocytosis by monocytes/macrophages, which may inhibit natural remyelination. Finally, through inducing formation of new mitochondria and increasing mitochondrial bulk in CNS cells may also have neuro-protective effects, especially on demyelinated axons, which have high energy demands. 3. Another process that correlates with MS severity (i.e., the speed of accumulation of neurological disability) is toxic astrogliosis. We performed high throughput screen of small molecules (most FDA-approved for varied indications) to identify inhibitors of the inflammation-induced transformation of astrocytes from normal, to neurotoxic phenotype. This screen identified dantrolene (and other drugs related to endoplasmic reticulum stress) as inhibitors of toxic astrocyte signature. Thus, TRAP-MS protocol tests the hypothesis that dantrolene will inhibit CSF biomarkers associated with toxic astrocytes and that this will lead to slowing of the disability accumulation. 4. Afore-mentioned processes are differentially expressed in individual patients and can be measured by cerebrospinal fluid (CSF) biomarkers. Therefore, CSF biomarkers may guide selection of optimal therapy and reflect its efficacy on residual MS activity. 5. To achieve high level of efficacy (ideally complete inhibition of MS progression) patients will need combination treatments that target all pathogenic mechanisms that are active in patients CNS. We expect that biomarker and mechanistic studies that accompany TRAP-MS trial will provide missing knowledge necessary for application of precision neurology in broad MS practice. We expect that not all drugs selected for initial testing in TRAP-MS trial will prove their desired efficacy in the intrathecal compartment and this protocol includes stopping criteria for individual drugs and their future replenishment with other candidate agents.