Our long-term goal is to understand the mechanisms that participate in central nervous system (CNS) injury and those that have neuroprotective functions to develop effective therapies for neuroimmunological diseases, especially multiple sclerosis (MS). Because observational studies cannot determine causal relationships, we use proof-of-principle interventional trials supported by biomarker/mechanistic studies and mathematical modeling to investigate major hypotheses about the pathophysiology of MS.
Our studies revealed that relapsing-remitting MS (RRMS) and progressive MS are categorical descriptions of early, versus evolved stages of the identical continuous disease process characterized by aberrant activation of adaptive immunity that targets CNS tissue, which evolves by progressive intrathecal compartmentalization and terminal differentiation of T and B cells to a treatment-resistant stage. The multiplicity of potential pathogenic processes in evolved MS makes it unlikely that a single therapeutic agent will have major clinical efficacy. Analogous to cardiovascular diseases, effective therapy will require combinations of therapeutics that target patient-specific drivers of disability. We believe that the development of such combination treatments requires the ability to reliably measure the diverse CNS pathophysiological processes in living people and thereby define process-specific biomarkers to use as outcomes in Phase II trials. Indeed, using cerebrospinal fluid (CSF) biomarkers and systems biology methodology we have defined (and validated in an independent cohort) molecular signature(s) that differentiate MS from other CNS diseases and those that can reliably measure the levels of intrathecally-compartmentalized inflammation and CNS tissue destruction. Our goal is to formulate (and validate) a framework where a combinatorial CSF biomarker(s) can provide reliable diagnostic, prognostic and therapeutically-predictive information that will empower neurologists to practice precision medicine.
- Barbour C, Kosa P, Komori M, Tanigawa M, Masvekar R, Wu T, Johnson K, Douvaras P, Fossati V, Herbst R, Wang Y, Tan K, Greenwood M, Bielekova B. Molecular-based diagnosis of multiple sclerosis and its progressive stage. Ann Neurol. 2017;82(5):795-812.
- Komori M, Blake A, Greenwood M, Lin YC, Kosa P, Ghazali D, Winokur P, Natrajan M, Wuest SC, Romm E, Panackal AA, Williamson PR, Wu T, Bielekova B. Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis. Ann Neurol. 2015;78(1):3-20.
- Natrajan MS, de la Fuente AG, Crawford AH, Linehan E, Nuñez V, Johnson KR, Wu T, Fitzgerald DC, Ricote M, Bielekova B, Franklin RJ. Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Brain. 2015;138(Pt 12):3581-97.
- Perry JS, Han S, Xu Q, Herman ML, Kennedy LB, Csako G, Bielekova B. Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis. Sci Transl Med. 2012;4(145):145ra106.
- Wuest SC, Edwan JH, Martin JF, Han S, Perry JS, Cartagena CM, Matsuura E, Maric D, Waldmann TA, Bielekova B. A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy. Nat Med. 2011;17(5):604-9.
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This page was last updated on Friday, August 2, 2019