From therapeutic mechanisms to unraveling the pathophysiology of MS

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

At disease onset, relapsing–remitting MS (RRMS) is marked by focal inflammatory lesions visible as MRI contrast-enhancing lesions (CELs). CELs reflect blood–brain barrier opening with an influx of immune cells. This focal inflammation damages the central nervous system (CNS), causing demyelination and axonal transection, and can produce acute neurological deficits (MS relapses). Because transected axons do not regenerate, each lesion leaves some irreversible injury, even when it isn’t immediately measurable as permanent disability. Current FDA-approved disease-modifying treatments (DMTs) suppress lesional activity (LA; CELs and relapses) by >90% and do so across all ages. Yet their impact on disability progression is much smaller and declines linearly with patient age. A meta-analysis of randomized trials indicates that when started after ~53 years of age, DMTs show no measurable effect on disability progression. Given the age distribution of MS, this implies that >40% of people living with MS lack effective options, and another large fraction derive suboptimal benefit. There is, therefore, a compelling need for treatments that target progression independent of lesional activity (PILA), which are the mechanisms driving disability without forming new lesions visible on MRI. What drives PILA remains uncertain. Pathology and CSF biomarker studies point to candidate processes, but causality requires interventional proof. Unfortunately, even the most sensitive clinical endpoints demand prohibitively large trials (≈1,000 patients followed >2 years) to detect a single-drug effect on progression—slowing therapeutic progress. A different path: TRAP-MS (NCT03109288). Our adaptive, platform Phase II trial "Targeting Residual Activity by Precision, biomarker-guided combination therapies of MS" (TRAP-MS) tests a new paradigm in patients who continue to worsen without new lesions despite DMTs (i.e., progressing by PILA). We use CSF biomarkers to (1) map patient-specific pathogenic mechanisms and (2) measure intrathecal pharmacodynamic effects of candidate drugs on those mechanisms. The guiding hypothesis, which is based on our research on CSF biomarkers and analogous to cardiovascular medicine, is that progressive MS is molecularly complex and heterogeneous, and that meaningful slowing of disability may require personalized, rational combinations that address multiple active pathways simultaneously. Research advances this review period (September 2024-August 2025): 1) Identifying pyroptosis as candidate Multiple sclerosis (MS) severity mechanism: Clemastine fumarate, an over-the-counter antihistamine that also blocks muscarinic acetylcholine receptors such as M1R, has shown promise in laboratory and early clinical studies for repairing myelin in people with MS (pwMS). Based on these findings, we tested clemastine in the TRAP-MS platform trial, to identify remyelination signature on CSF biomarkers and to extent safety and efficacy data to pwMS progressing by PILA. The clemastine arm was stopped early when one-third of participants met strict safety-stopping criteria for unusually rapid disability progression. Compared with patients receiving other TRAP-MS drugs, clemastine-treated participants worsened faster, developed metabolic changes, and showed signs of increased systemic inflammation. Using advanced proteomic analysis of cerebrospinal fluid (CSF), we discovered that clemastine amplified purinergic signaling and triggered pyroptosis, a form of inflammatory cell death, within the CNS. Laboratory experiments confirmed that clemastine, in the presence of danger signal ATP , prolonged opening of the P2RX7 channel, causing pyroptotic death of both immune cells and human oligodendrocytes (the cells that make myelin). A selective P2RX7 inhibitor blocked this toxic effect. Re-analysis of single-nucleus RNA sequencing data from MS brain tissue revealed that microglia and a specific oligodendrocyte subtype, both abundant in progressive MS lesions, show high P2RX7 expression and strong pyroptosis signatures. We also developed a CSF pyroptosis score, which was significantly increased in people with MS (pwMS)compared to controls, higher in progressive MS than in relapsing-remitting MS, correlated with MS severity measured as the rate of disability accumulation, and was further elevated by clemastine treatment. Our findings showcase that off-label use of FDA-approved drugs, even if these are available over-the-counter like clemastine fumarate, have potential for off-target toxicity when applied to previously untested populations such as people with progressive neurological diseases. Importantly, we identified P2RX7-linked pyroptosis as a likely driver of MS disability progression even outside of clemastine exposure. The CSF pyroptosis score can now help pinpoint patients who might benefit from future trials of brain-penetrant P2RX7 inhibitor(s), which is currently being tested for efficacy on limiting depression. (2) Identifying beneficial pharmacodynamic effects of pioglitazone on CSF biomarkers and biomarker models that correlate with MS severity. This finding moves pioglitazone to second stage of TRAP-MS protocol where we'll assess its efficacy on MS severity (clinical) outcome.