Biomarkers of Therapeutic Response in Multiple Sclerosis: Current Status

Abstract

Multiple sclerosis (MS) is an autoimmune disease of unknown cause, in which chronic inflammation drives multifocal demyelination of axons in both white and gray matter in the CNS. The pathological course of the disease is heterogeneous and involves an early, predominantly inflammatory demyelinating disease phase of relapsing–remitting MS (RRMS), which, over a variable period of time, evolves into a progressively degenerative stage associated with axonal loss and scar formation, causing physical and cognitive disability. For patients with RRMS, there is a growing arsenal of disease-modifying agents (DMAs), with varying degrees of efficacy, as defined by reduced relapse rates, improved magnetic resonance imaging outcomes, and preservation of neurological function. Establishment of personalized treatment plans remains one of the biggest challenges in therapeutic decision-making in MS because the disease prognosis and individual therapeutic outcomes are extremely difficult to predict. Current research is aimed at discovery and validation of biomarkers that reliably measure disease progression and effective therapeutic intervention. Individual biomarker candidates with evident clinical utility are highlighted in this review and include neutralizing autoantibodies against DMAs, fetuin-A, osteopontin, isoprostanes, chemokine (C-X-C motif) ligand 13 (CXCL13), neurofilament light and heavy, and chitinase 3-like protein. In addition, application of more advanced screening technologies has opened up new categories of biomarkers that move beyond detection of individual soluble proteins, including gene expression and autoantibody arrays, microRNAs, and circulating microvesicles/exosomes. Development of clinically useful biomarkers in MS will not only shape the practice of personalized medicine but will also serve as surrogate markers to enable investigation of innovative treatments within clinical trials that are less costly, are of shorter duration, and have more certainty of outcomes.

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

“…SOD1 (superoxide dismutase 1) and Prx (peroxiredoxin) families which were particularly affected in patient-derived iPS cells are expected to be clinical biomarkers in assessing efficiency of drug therapy. Circulating microvesicles/exosomes and specific microRNAs are also potent biomarkers with promising therapeutic applications in diseases such as multiple sclerosis [53] or liver injury [54]. Imaging, as well as physiological and functional measurements are also valuable biomarkers for hypothesis confirmation; however, assessing indicators usually requires a special set of skills and instruments.…”

Utility of Autoantibodies as Biomarkers for Diagnosis and Staging of Neurodegenerative Diseases

“…This condition falls into this next category where autoantibodies play a largely contentious role in what was once thought to be a clearly defined relationship (Mirshafiey & Kianiaslani, 2013;Terryberry, Thor, & Peter, 1998). Indeed, the immune system effector T cells are integral to the development of this disease, while the presence and detection of autoantibody to various neuronal and myelin proteins have remained scattered from causative, to prognostic, to diagnostic among the medical community (Harris & Sadiq, 2014).…”

“…The identification of MS, today's most common debilitating CNS autoimmune disease, is predated by over 150 years of clinical classification (Harris & Sadiq, 2014). The common early symptoms of extremity muscle weakness and paresthesias, blurred vision, and cognitive decline manifest from CNS (2011) Melanin Double et al (2009) neuronal demyelination, which first occurs in the white matter of the brain (including the optic nerve) and spinal cord, but later includes gray matter lesions (Harris & Sadiq, 2014;Jurynczyk, Craner, & Palace, 2015).…”

“…The common early symptoms of extremity muscle weakness and paresthesias, blurred vision, and cognitive decline manifest from CNS (2011) Melanin Double et al (2009) neuronal demyelination, which first occurs in the white matter of the brain (including the optic nerve) and spinal cord, but later includes gray matter lesions (Harris & Sadiq, 2014;Jurynczyk, Craner, & Palace, 2015). Lesions are typically found to contain clonal populations of B cells and plasma cells, CD4 + autoreactive T cells, and autoantibodies.…”

Targeting CXCL13 During Neuroinflammation

“…Even in cases of progressive MS where the long-term clinical benefits of such immunotherapies are unclear, CSF levels of CXCL13 still consistently fall after 6 months of systemic treatment with compounds that blocks lymphocyte entry into the CNS [78]. Together, these data suggest that changes in intrathecal CXCL13 concentrations may reflect lymphocyte traffic through the CNS more than local glial production, and that such changes also serve as a potential biomarker of treatment responsiveness across the spectrum of MS subtypes [79]. …”