An appraisal of emerging therapeutic targets for multiple sclerosis derived from current preclinical models

ABSTRACT

Introduction

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating, and neurodegenerative condition affecting the central nervous system (CNS). Although therapeutic approaches have become available over the last 20 years that markedly slow the progression of disease, there is no cure for MS. Furthermore, the capacity to repair existing CNS damage caused by MS remains very limited.

Areas covered

Several animal models are widely used in MS research to identify potential druggable targets for new treatment of MS. In this review, we look at targets identified since 2019 in studies using these models, and their potential for effecting a cure for MS.

Expert opinion

Refinement of therapeutic strategies targeting key molecules involved in the activation of immune cells, cytokine, and chemokine signaling, and the polarization of the immune response have dominated recent publications. While some progress has been made in identifying effective targets to combat chronic demyelination and neurodegeneration, much more work is required. Progress is largely limited by the gaps in knowledge of how the immune system and the nervous system interact in MS and its animal models, and whether the numerous targets present in both systems respond in the same way in each system to the same therapeutic manipulation.

KEYWORDS:

• Multiple sclerosis
• preclinical models
• experimental autoimmune encephalomyelitis
• cuprizone-induced demyelination
• polarization of immune response
• Regulatory T cells
• CNS repair
• remyelination

Article highlights

• Multiple sclerosis is a chronic neurological disorder involving distinct pathways and processes in the periphery and the CNS, each of which could potentially be targeted for therapeutic intervention

• Several preclinical small animal models are available to model these different processes, but they do have limitations: it is critical to select the most appropriate model based on the pathogenic process that is being targeted

• Targeting innate immune cells and polarization of the immune response are effective in preventing peripheral immune responses, but further work is required to confirm their utility in the CNS

• All studies in this field should aim to show efficacy in a therapeutic, not just prophylactic, setting

• There are still only limited studies on therapeutic targets for effecting CNS repair: this remains the area of greatest need for future effective interventions for multiple sclerosis

Declaration of Interest

JM Greer has received an investigator-initiated grant from Merck KGaA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded by the National Health and Medical Research Council of Australia Grant 1182096.