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Charlene Cui, Jing Wang, Ariana P Mullin, Anthony O Caggiano, Tom J Parry, Raymond W Colburn, Elias Pavlopoulos
Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the CNS. In addition to motor, sensory and visual deficits, MS is also characterized by hippocampal demyelination and memory impairment. We recently demonstrated that a recombinant human-derived monoclonal IgM antibody, which is designated rHIgM22 and currently in clinical development for people with MS, accelerates remyelination of the corpus callosum in the brains of cuprizone-treated mice. Here, we investigated the effects of rHIgM22 in the hippocampus and on hippocampal-dependent learning and memory in the same mouse model of cuprizone-induced demyelination and spontaneous remyelination...
May 15, 2018: Brain Research
Maria K Perwein, John A Smestad, Arthur E Warrington, Robin M Heider, Mark W Kaczor, Louis J Maher, Bharath Wootla, Ahmad Kunbaz, Moses Rodriguez
Multiple sclerosis (MS) is a chronic and progressive inflammatory demyelinating disease of the human central nervous system (CNS) and is the most common disabling neurological condition in young adults, resulting in severe neurological defects. No curative or long-term progression-inhibiting therapy has yet been developed. However, recent investigation has revealed potential strategies that do not merely modulate potentially pathogenic autoimmune responses, but stimulate remyelination within CNS lesions. Areas covered: We discuss the history and development of natural human IgM-isotype immunoglobulins (HIgMs) and recently-identified aptamer-conjugates that have been shown to enhance endogenous myelin repair in animal models of demyelination by acting on myelin-producing oligodendrocytes (OLs) or oligodendrocyte progenitor cells (OPCs) within CNS lesions...
February 25, 2018: Expert Opinion on Biological Therapy
Andrew Eisen, Benjamin M Greenberg, James D Bowen, Douglas L Arnold, Anthony O Caggiano
Objective: The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22). Methods: Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months...
October 2017: Multiple Sclerosis Journal—Experimental, Translational and Clinical
Ariana P Mullin, Charlene Cui, Yu Wang, Jing Wang, Erika Troy, Anthony O Caggiano, Tom J Parry, Raymond W Colburn, Elias Pavlopoulos
Failure of oligodendrocyte precursor cells (OPCs) to differentiate and remyelinate axons is thought to be a major cause of the limited ability of the central nervous system to repair plaques of immune-mediated demyelination in multiple sclerosis (MS). Current therapies for MS aim to lessen the immune response in order to reduce the frequency and severity of attacks, but these existing therapies do not target remyelination or stimulate repair of the damaged tissue. Thus, the promotion of OPC differentiation and remyelination is potentially an important therapeutic goal...
September 2017: Neurobiology of Disease
Hernan Nicolas Lemus, Arthur E Warrington, Aleksandar Denic, Bharath Wootla, Moses Rodriguez
A single peripheral dose of CNS-binding IgMs promote remyelination and preserve axons in a number of animal models of neurologic disease. A myelin-binding recombinant human IgM (rHIgM22) is presently in a safety trial in MS patients following an acute MS exacerbation. rHIgM22 (directed against oligodendrocytes) or rHIgM12 (directed against neurons) were administered to mice with MOG-induced experimental autoimmune encephalomyelitis (EAE) with study endpoints: clinical deficits and brain and spinal cord pathology...
2017: Human Antibodies
Harika Dasari, Bharath Wootla, Arthur E Warrington, Moses Rodriguez
We provide an overview of rehabilitation in neurological diseases. A large amount of literature available on neurorehabilitation is based from the rehabilitative work on stroke and spinal cord injuries. After a brief description of rehabilitation, the potential application of neurorehabilitation in neurodegenerative diseases specifically multiple sclerosis (MS) is summarized. Since MS causes a wide variety of symptoms, the rehabilitation in MS patients may benefit from an interdisciplinary approach that encloses physiotherapy, cognitive rehabilitation, psychological therapy, occupational therapy, and other methods to improve fatigue...
August 2016: International Journal of Physical Medicine & Rehabilitation
Barry A Singer
Improved disease control is critical for enhancing the lives of those living with multiple sclerosis. With specific immunologic targets, monoclonal antibody (mAb) treatments are highly effective options for relapsing forms of multiple sclerosis. The mechanism, efficacy, and current safety profiles are detailed for the two mAb therapies, natalizumab and alemtuzumab, with regulatory approval in multiple countries. Daclizumab, which targets the interleukin-2 receptor, and ocrelizumab, which depletes B cells, have convincing phase 3 clinical trial data and may very well provide new options in the near future...
April 2016: Seminars in Neurology
Bharath Wootla, Aleksandar Denic, Jens O Watzlawik, Arthur E Warrington, Moses Rodriguez
Demyelination underlies early neurological symptoms in multiple sclerosis (MS); however, axonal damage is considered critical for permanent chronic deficits. The precise mechanisms by which axonal injury occurs in MS are unclear; one hypothesis is the absence or failure of remyelination, suggesting that promoting remyelination may protect axons from death. This report provides direct evidence that promoting oligodendrocyte remyelination protects axons and maintains transport function. Persistent Theiler's virus infection of Swiss Jim Lambert (SJL)/J mice was used as a model of MS to assess the effects of remyelination on axonal injury following demyelination in the spinal cord...
October 2016: Molecular Neurobiology
Jens O Watzlawik, Arthur E Warrington, Moses Rodriguez
BACKGROUND: Promotion of remyelination is a major goal in treating demyelinating diseases such as multiple sclerosis (MS). The recombinant human monoclonal IgM, rHIgM22, targets myelin and oligodendrocytes (OLs) and promotes remyelination in animal models of MS. It is unclear whether rHIgM22-mediated stimulation of lesion repair is due to promotion of oligodendrocyte progenitor cell (OPC) proliferation and survival, OPC differentiation into myelinating OLs or protection of mature OLs...
2013: PloS One
J Watzlawik, E Holicky, D D Edberg, D L Marks, A E Warrington, B R Wright, R E Pagano, M Rodriguez
PURPOSE: Human remyelination promoting IgM mAbs target oligodendrocytes (OLs) and function in animal models of multiple sclerosis (MS). However, their mechanism of action is unknown. This study seeks to identify the cellular mechanism of action of a recombinant human IgM on OL survival. METHODS: Binding of rHIgM22 to the surface of rat OLs was studied by co-localization with various markers. RHIgM22-mediated effects on apoptotic signaling in OLs, differentiation markers, and signaling molecules were detected by Western blotting and immunoprecipitation...
November 15, 2010: Glia
Arthur E Warrington, Moses Rodriguez
INTRODUCTION: Natural autoantibodies are part of the normal human immunoglobulin repertoire. These antibodies react to self-antigens, are usually polyreactive with relatively low affinity, and typically are of the IgM isotype. Natural IgMs in mice that stimulated remyelination in central nervous system (CNS) demyelinating disease all shared the characteristics of binding to the surface of live oligodendrocytes and myelinated tracts in living slices of CNS tissue. METHODS: A screen for human IgMs with similar character resulted in two human natural antibodies, which when injected peripherally into animal models of demyelination induced remyelination...
May 2010: Journal of Clinical Immunology
Moses Rodriguez, Arthur E Warrington, Larry R Pease
Naturally occurring autoantibodies are molecules that are part of the normal immunoglobulin repertoire. This review focuses on three distinct groups of human monoclonal antibodies (mAb). These are human natural autoantibodies that, when injected into an animal model of human disease, stimulate remyelination in CNS demyelinating diseases, protect neurons and extend neuronal processes in CNS axonal disorders, and activate immune dendritic cells to produce cytotoxic T cells to clear metastatic tumors. Natural autoantibodies react to self antigens and are of relatively low affinity...
April 7, 2009: Neurology
A E Warrington, M Rodriguez
Promoting remyelination following injury to the central nervous system (CNS) promises to be an effective neuroprotective strategy to limit the loss of surviving axons and prevent disability. Studies confirm that multiple sclerosis (MS) and spinal cord injury lesions contain myelinating cells and their progenitors. Recruiting these endogenous cells to remyelinate may be of therapeutic value. This review addresses the use of antibodies reactive to CNS antigens to promote remyelination. Antibody-induced remyelination in a virus-mediated model of chronic spinal cord injury was initially observed in response to treatment with CNS reactive antisera...
2008: Current Topics in Microbiology and Immunology
Arthur E Warrington, Allan J Bieber, Bogoljub Ciric, Larry R Pease, Virginia Van Keulen, Moses Rodriguez
A recombinant human monoclonal IgM, rHIgM22, promotes the synthesis of new myelin when used to treat several animal models of demyelination. rHIgM22 binds to myelin and the surface of oligodendrocytes and accumulates at central nervous system lesions in vivo. The minimal dose of monoclonal IgM required to promote remyelination has a direct bearing on the proposed mechanism of action. A dose ranging study using rHIgM22 was performed in mice with chronic virus-induced demyelination, a model of chronic progressive multiple sclerosis...
April 2007: Journal of Neuroscience Research
Istvan Pirko, Bogoljub Ciric, Jeff Gamez, Allan J Bieber, Arthur E Warrington, Aaron J Johnson, Dennis P Hanson, Larry R Pease, Slobodan I Macura, Moses Rodriguez
The human monoclonal antibody rHIgM22 enhances remyelination following spinal cord demyelination in a virus-induced murine model of multiple sclerosis. Using three-dimensional T2-weighted in vivo spinal cord magnetic resonance imaging (MRI), we have therefore assessed the extent of spinal cord demyelination, before and after 5 weeks of treatment with rHIgM22, to determine whether antibody enhanced remyelination can be detected by MRI. A significant decrease was seen in T2 high signal lesion volume following antibody treatment...
October 2004: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Charles L Howe, Allan J Bieber, Arthur E Warrington, Larry R Pease, Moses Rodriguez
Stabilizing the survival of oligodendrocytes and oligodendrocyte precursors within and near lesions in patients suffering from multiple sclerosis (MS) and other demyelinating diseases is an important therapeutic goal. Previous studies have identified a human-derived monoclonal IgM antibody designated rHIgM22 that induces remyelination in a mouse model of MS. We provide evidence that this antibody, directed against myelin, induces antiapoptotic signaling in premyelinating oligodendrocytes and reduces caspase-3 activation and caspase gene expression in mice undergoing antibody-induced remyelination...
February 2004: Neurobiology of Disease
Bogoljub Ciric, Virginia Van Keulen, Mateo Paz Soldan, Moses Rodriguez, Larry R Pease
A set of antibodies capable of binding glial cells promotes remyelination in models of multiple sclerosis (MS). Within this set, the mouse antibody, SCH94.03, was immunomodulatory implying that immune system mobilization might be integral to remyelination. We evaluated whether the human remyelination-promoting antibody rHIgM22 influences acquired immunity. The antibody did not bind to immune cells, or influence humoral immune responses, antigen presentation, T cell proliferation or cytokine production. Treatment with rHIgM22 had no effect on demyelination or virus infection in two disease models...
January 2004: Journal of Neuroimmunology
Yoshihiro Mitsunaga, Bogoljub Ciric, Virginia Van Keulen, Arthur E Warrington, Mateo Paz Soldan, Allan J Bieber, Moses Rodriguez, Larry R Pease
Certain human sera from patients with monoclonal gammopathies contain factors that induce myelin repair in animals with demyelinating disease. We hypothesize that antibodies functionally distinguish the serum of one patient from another. However, pooled normal polyclonal human IgM antibodies also induce remyelination. Definitive proof that specific antibodies are the biologically active components of serum is missing because unquestionably pure preparations of antibody molecules cannot be generated by fractionation...
August 2002: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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