Translational Neuroimmunology in Multiple Sclerosis

From Disease Mechanisms to Clinical Applications

Ruth Arnon, Ariel Miller

• Publisher: Academic Press
• Year: 2016
• Print ISBN: 9780128019146
• eBook ISBN: 9780128020074
• Topic: Medicine
• Subtopic: Immunology

Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. More than 2.3 million people are affected by MS worldwide. Symptoms can vary widely, depending on the localization and amount of the damage induced by combined inflammatory, demyelinating, and neurodegenerative processes. Although a cure for MS does not currently exist, therapies can help treat MS attacks, attenuate disease activity, reduce progress of the disease, and manage symptoms. Translational Neuroimmunology in Multiple Sclerosis provides an overview of recent findings and knowledge of the neuroimmunology of multiple sclerosis, from experimental models and the human disease to the translation of this research to immunotherapeutic strategies. Chapters describe genetic and environmental factors underlying the disease pathogenesis of MS as a basis for development of immunotherapies, immunological markers of disease activity, pharmacogenetics, and responses to therapy. Immunomodulatory therapies currently in practice and future therapeutic strategies on the horizon—such as neuroprotective strategies, stem cells, and repair promotion—are discussed. Contributed by renowned leaders in the field, this cross-disciplinary volume is a great resource for basic scientists and clinical practitioners in neuroscience, neurology, immunology, pharmacology, and in-drug development. - Provides an overview of recent findings and knowledge of the neuroimmunology of multiple sclerosis and the translation of this research to immunotherapy treatment - Edited by renowned leaders in the field of neuroimmunology and multiple sclerosis - Contains the latest resource material for basic and clinical scientists and practitioners in neuroscience, neurology, immunology, and pharmacology - 2017 BMA Medical Book Awards Highly Commended in Neurology

Section VII

Novel & Emerging Strategies

Outline

Chapter 26. Personalized Medicine and Theranostics: Applications to Multiple Sclerosis

Chapter 27. Stem Cell-Based Therapies, Remyelination, and Repair Promotion in the Treatment of Multiple Sclerosis

Chapter 28. Stem Cells in Multiple Sclerosis

Chapter 29. T-Cell Vaccination: An Insight Into T-Cell Regulation

Chapter 30. Reversal of Misfortune: Therapeutic Strategies on the Horizon

Chapter 26

Personalized Medicine and Theranostics

Applications to Multiple Sclerosis

T. Paperna, E. Staun-Ram, N. Avidan, and I. Lejbkowicz Technion-Israel Institute of Technology, Haifa, Israel

A. Miller Technion-Israel Institute of Technology, Haifa, Israel Carmel Medical Center, Haifa, Israel

Abstract

Tailored therapeutics based on diagnostic tests—theranostics—is shaping future health care. We describe recent progress in the search for biomarkers for multiple sclerosis (MS) related to drug response. Robust and clinically validated predictive biomarkers for support of treatment optimization are of increased need, especially as the treatment options increase, to improve efficacy and safety as part of tailored therapeutics. Pharmacogenomic studies in MS were mainly focused on biomarkers for interferon beta response, and none of the markers has translated into clinical practice. The antibody-based tests for John Cunningham virus have been clinically validated and are implemented in clinical practice to aid care for natalizumab-treated patients. Participatory medicine empowers patients to be actively involved in their care by tailored medical information, according to their needs and expectations. It can increase adherence and, together with the biomarkers in development, contribute to improved health care of the patient with MS.

Keywords

Biomarker; Drug adherence; Drug response; Personalized medicine; Pharmacogenomics

Outline

26.1 Personalized Medicine in Multiple Sclerosis: The Need

26.2 Biomarkers in Use for the Diagnosis of Multiple Sclerosis

26.2.1 Oligoclonal Bands and MRI

26.2.2 Aquaporin-4 Autoantibodies for Differential Diagnosis in Multiple Sclerosis

26.3 Biomarkers for Response to Therapy and for Treatment Safety

26.3.1 Interferon-β

Protein-Based Markers in Interferon-β Therapy

Pharmacogenetic Studies for Interferon-β Response

RNA Expression-Based Markers for Interferon-β Response

MicroRNAs as Biomarkers for Interferon-β Response

Biomarkers for Adverse Response to Interferon-β

26.3.2 Glatiramer Acetate

Protein-Based Markers in Glatiramer Acetate Therapy

Pharmacogenetic Studies for Glatiramer Acetate Response

Gene Expression Studies for Clinical Response to Glatiramer Acetate

Biomarkers for Adverse Response in Glatiramer Acetate Therapy

26.3.3 The Oral Multiple Sclerosis Drugs: Fingolimod, Teriflunomide, and Dimethyl Fumarate

26.3.4 Natalizumab

Protein-Based Markers in Natalizumab Therapy

Biomarkers for Natalizumab-Related Adverse Response

26.3.5 Immunosuppressant Therapy for Multiple Sclerosis: Mitoxantrone and Alemtuzumab

Mitoxantrone

26.4 Participatory Medicine and Personalized Information in Multiple Sclerosis

26.5 Conclusions

References

Care of the patient with multiple sclerosis (MS) has made considerable progress in the 2000s, including the increased accuracy in diagnosis of the disease, and the availability of new therapies for patients with relapsing MS (PwRMS). Currently, the key challenge in the application of optimized care for the patient with MS (PwMS) is the implementation of the personalized medicine-based approach, namely, choosing the right drug at the right dose, for the right patient at the right time and cost. This approach of tailored therapeutics based on diagnostic tests, called theranostics, consists of some cardinal conceptual changes in the mode of care in the field of MS: shifting paradigms from medical practice based on trial and error to medical practice based on predictive measures and biomarkers, moving from reactive to proactive medical care, and moving from treating the disease to treating the patient.

26.1. Personalized Medicine in Multiple Sclerosis: The Need

Approved therapies include the injectable interferon β (IFN-β) therapies and glatiramer acetate (GA), the oral therapies dimethyl fumarate (DMF), teriflunomide, fingolimod alemtuzumab for active disease, natalizumab, and other immunosuppressants such as mitoxantrone for refractory MS. Several potential therapies are currently being evaluated in clinical trials and will increase the armamentarium for MS in the future. The variety of therapy options is a benefit and a challenge for the PwRMS and the treating physician.

As for most drugs, response to MS therapies varies from individual to individual. Response variability has two aspects: efficiency and safety. Some PwRMS may show a clear beneficial effect for a specific therapy while for others the same therapy may fail to attenuate disease activity and disability accumulation. MS disease heterogeneity is well recognized and may reflect disease pathomechanisms in different patients, and may explain some of the therapy failures: Therapies targeting specific pathological pathways may be effective solely for individuals with a specific MS subtype. Currently, as neither the underlying pathologies responsible for MS disease subtypes are fully understood, nor are criteria available to distinguish disease subtypes beyond the basic clinical definition of relapsing and progressive MS¹; the targeting of MS subtypes with specific drug(s) (monotherapy or combination therapy) for the specific patient is not yet possible. Variability in efficiency of response is suggested to be caused by inherent differences between individuals that are determined by genetic and environmental exposures.

Adverse events (AEs) are experienced by some PwRMS and are a serious concern, as they can be severe and even fatal. AEs are usually drug-specific and not related to disease subtype. Three MS therapies, natalizumab, alemtuzumab, and mitoxantrone, were issued a black-box warning by the Food and Drug Administration (FDA)^2–4: mitoxantrone for cardiotoxicity and risk of secondary leukemia; natalizumab for the risk of progressive multifocal leukoencephalopathy (PML); and alemtuzumab for risk of serious and fatal autoimmune reactions, infusion reactions, and malignancy. However, other MS therapies also have severe AEs associated with their use. For example, cardiovascular AEs can occur with fingolimod therapy, and elevation of liver enzymes is a well-recognized effect of the IFN-β therapies.⁵ Beyond the devastating health complications of AEs for PwRMS, AEs present a significant economic burden to the health-care system as they incur additional hospitalizations and medical care.

Much effort over the years has been devoted to the identification of predictive and prognostic markers, with high sensitivity and specificity, to aid and guide MS diagnosis and therapy prescription. Ideally such markers should be detected in easily accessible bodily fluids, such as blood and its derived products—serum and plasma, urine, and saliva. Recently, the rising recognition of the role of the microbiome in disease suggests stool samples may be a source for biomarkers. Factors that determine the potential of a biomarker for translation from the basic science bench to the clinical lab include the stability of the biomarker and reproducibility across measurements and between laboratories, the level of expertise required for the bioassay, the invasiveness of the test, and last ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Section I. MS Pathology and Mechanisms
• Section II. Other Patho-Mechanisms
• Section III. Surrogate Markers in Multiple Sclerosis
• Section IV. Currently Approved Therapies—Injectable
• Section V. Currently Approved DMDs-Oral
• Section VI. Symptomatic & Complementary Treatments
• Section VII. Novel & Emerging Strategies
• Index