Emerging Drugs and Targets for Multiple Sclerosis

Ana Martinez

• Publisher: Royal Society of Chemistry
• Year: 2019
• Print ISBN: 9781788014502
• eBook ISBN: 9781788018067
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Biochemistry

Multiple sclerosis (MS) is a complex disease with a presumed autoimmune aetiology and few current effective treatments. Disease modifying therapies focus on the altering the natural course of relapsing and remitting MS, targeting the inflammatory response. Other targets involve tacking the cause of the disease – demyelination of axons through remyelination therapies. Due to several recent breakthroughs in the understanding of the pathophysiology of MS new targets for remyelination and immunomodulation are rapidly emerging. This book provides a comprehensive overview of drug discovery and development for the molecular basis of the disease, from new targets to drugs currently in clinical development, cellular and animal disease models to biomarkers for diagnosis and assessment in clinical trials. Emerging Drugs and Targets for Multiple Sclerosis is an ideal reference for any student or researcher interested in drug development for neurodegenerative diseases, autoimmune diseases and MS in particular.

Part I: General Information

CHAPTER 1

Multiple Sclerosis: Epidemiology, Genetics, Symptoms, and Unmet Needs

Irene Moreno-Torres^{a ,b}, Julia Sabín-Muñoz^c and Antonio García-Merino^{*a ,b ,c}

^a Neuroimmunology Unit, Puerta de Hierro-Segovia de Arana Health Research Institute, Manuel de Falla 1, 28222 Madrid, Spain

^b Autonomous University of Madrid, Madrid, Spain

^c Puerta de Hierro University Hospital, Neuroimmunology Unit, Manuel de Falla 1, 28222 Madrid, Spain
^*E-mail: [email protected]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system. MS is more prevalent in women and is estimated to affect some 2.3 million people across the world. There is unequivocal genetic susceptibility in MS. The most consistent genetic determinant identified is the major histocompatibility complex (MHC). The haplotypes more strongly related to susceptibility and protection for MS are HLA-DR2 and HLA-DR11, respectively. Some genes outside the MHC, such as IL2RA, IL7R and TNFRSF1A, have also been related to MS. There is a latitudinal gradient of MS prevalence, probably due to environmental factors on the genetic susceptibility. The most important MS risk factors are seropositivity against Epstein–Barr virus, infectious mononucleosis, and smoking. Other factors such as vitamin D or parasitic infections require further investigation. The clinical manifestations of relapsing forms of MS in initial stages are related to demyelination of the susceptible structures such as the optic nerves or spinal cord. In established MS, the clinical symptoms are related to the multisystemic affectation and neurodegeneration such as cognitive impairment or sphincter disorders. An unmet need exists for highly effective medications with low risk for deep immunosuppression and for the symptomatic relief of MS.

1.1 Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS)¹ and is thought to be autoimmune in nature. It is characterized by the appearance of areas of demyelination in the white and gray substances of the CNS,² infiltration of inflammatory cells in the parenchyma, glial reaction, and axonal damage.^3,4 All these processes occur from the early stages of the disease with the consequent accumulation of disability.

Although the underlying cause of MS still remains unknown, there is increasing evidence that immune dysregulation may play a role in genetically susceptible individuals. Some risk factors related to immune dysregulation have been identified, such as infections (Epstein–Barr virus, varicella/zoster, and HHV-6), environmental factors (latitude, vitamin D), and epigenetic factors (post-genomic rearrangements or somatic mutations). The sum of one or more risk factors on a genetic susceptibility leads to the loss of homeostasis between the inflammatory response and self-tolerance, tilting the balance towards autoimmunity directed against the CNS.³

Between 1831 and 1842, Robert Carswell and Jean Cruveilhier presented their collections of autopsy material of MS patients in London and Paris, respectively. They described in vivo the brain lesions on plates for the first time. Cruveilhier was the first to relate these lesions to clinical findings and called it the medullar disease with paraplegia. Despite some preliminary clinical descriptions, made by Friedrich Theodor von Frerichs (1849), his pupil Valentiner (1856), Carl Rokitansky (1857) and Eduard Rindfleisch (1863), it was not until 1865 when Jean-Martin Charcot made the first detailed description of the disease.⁵ This description included plaque-like lesions disseminated in time and space with a predominant myelin involvement, mainly in the optic nerve, the periventricular region, and spinal cord, which were correlated with clinical manifestations alternating periods of exacerbation and remission. He explained the most characteristic clinical signs of the disease: oculomotor disorders, ataxia and dysarthria. In this way, MS was recognized for the first time as an entity distinct from other diseases.

The term “sclérose en plaques disseminées” was coined by Edmé Félix Alfred Vulpian in 1866.⁶ Later, his friend and collaborator Charcot reduced the term to “sclérose en plaques,” and the term “multiple sclerosis” was introduced in the medical literature by Edward Seguin in 1878,⁵ but it was not until McAlpine, Compston, and Lumsden's classic publication in 1955 that the term gained international usage.

In Diseases of the Nervous System, a book published in 1933, the author Russell Brain reported data on the incidence and course of MS, together with precise explanations on the underlying pathophysiology, some of which continue to be valid today. Since then, a series of clinical criteria have been used and updated periodically to make the diagnosis of the disease.⁷ Magnetic resonance imaging (MRI) techniques and cerebrospinal fluid (CSF) analysis have been incorporated into the diagnostic algorithms. This has allowed an improvement in the criteria sensitivity and specificity, resulting in the current McDonald criteria 2017.⁴

1.2 Epidemiology and Genetics of Multiple Sclerosis

Age at onset of MS can vary from childhood to adult life, and the average is between 20 and 40 years. MS is the first cause of non-traumatic disability in young patients, which has a great impact on the quality of life, a high health cost, and important social repercussions.⁸ MS is estimated to affect some 700 000 people in Europe and 2.3 million across the world. Longitudinal studies have revealed an increase in MS prevalence in recent years, but this does not necessarily carry an increased risk of MS. The increase in prevalence is related to a higher life expectancy in MS patients (as in the general population) over the last decades as a result of the improvement in healthcare, better disability rehabilitation, and access to health resources. The continuous review of McDonald's criteria has allowed earlier diagnosis, which also increases the incidence of MS. An increase in Europe and North America of 0.064 per 100 000 each year has been reported.⁹ MS patients have a 7-year shorter life expectancy and two to three times higher mortality compared with the general population.¹⁰

MS is universally found to be more prevalent in women than men, and the MS prevalence ratio of women to men has increased markedly during the last 60 years.^9,11 According to a Canadian study published in 2006, the sex ratio increased from 2 : 1 in 1936–1940 to 3.2 : 1 in 1976–1980.¹² Similar data supporting this increase have been published by other groups in Germany, France, and Norway.^9,11,13 An analysis carried out in Europe and the United States indicated that the sex ratio not only changes over time but has also been shown to be negatively correlated with latitude.⁹

There is unequivocal evidence to support genetic susceptibility as an important factor involved in the occurrence of MS. In the general population, the MS risk is about 0.1–0.25%¹³ and increases up 2–5% in individuals with an affected family member in proportion to the number of shared genes. The published study with the largest number of patients in this regard involved 15 000 Canadian patients with MS and their families.¹⁴ It has been demonstrated that first-degree relatives (parents, children, and siblings) of an affected individual have a risk of approximately 2–5%, which can increase up to 30% if both parents are affected or up to 27% in monozygotic twins. The concordance between dizygotic twins is 3.5%, and up to 14% of asymptomatic monozygotic twins have MRI lesions compatible with demyelination. Second-degree relatives (aunts and uncles) have a risk of about 1–2%, and third-degree relatives (cousins) have a risk of less than 1%. The risk of MS decreases with age, and after 43 years it does not exceed 0.5%. A variation in MS risk has also been observed according to geographic area, being 2.4% in high prevalence areas and 0.1% in low prevalence areas.¹⁴

It has been suggested that the origin of the disease is the result of genetic mutations in the Scandinavian population during the first millennium, which were spread through the offspring by the Vikings during invasions and migrations to the rest of the known world.¹⁵ This...

Table of contents

• Cover
• halftitle
• series Editor
• Title
• Copyright
• Preface
• Contents
• Part I: General Information
• Chapter 1 Multiple Sclerosis: Epidemiology, Genetics, Symptoms, and Unmet Needs 3