Developing Therapeutics for the Treatment of Multiple Sclerosis

doi:10.1602/neurorx.2.4.638
Copyright © 2005 The American Society for Experimental NeuroTherapeutics, Inc. Published by Elsevier Inc. - Science Direct

David J. Virley Ph.D.^{, a,}

^aNeurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM19 5AW, United Kingdom

Available online 3 March 2006.

Summary

Multiple sclerosis (MS) is both a complex and chronic neurological disease of the CNS. This poses unique challenges for drug discovery in terms of delineating specific targets related to disease mechanisms and developing safe and effective molecules for clinical application. Preclinical animal models of MS provide the necessary test bed for evaluating the effects of novel therapeutic strategies. Because the clinical manifestations and pathological consequences of disease vary dramatically from individual to individual, as well as treatment response to existing therapies, this creates a significant research endeavor in terms of translating preclinical methodologies to the clinical domain. Potentially exciting treatments have emerged in the form of natalizumab (Tysabri), an α4 integrin antagonist, and more recently FTY720, a sphinogosine-1 phosphate receptor modulator, providing a compelling proof-of-principle from bench to bedside. However, further research is required to discharge safety concerns associated with these therapeutic avenues. Future prospects in the guise of disease-modifying therapies that target the inflammatory and neurodegenerative components of disease have come to the forefront of preclinical research with the sole aim of reducing the underlying irreversible progressive disability of MS. Significant progress with novel therapies will be made by implementing biomarker strategies that extrapolate robustly from animal models to the divergent patient populations of MS. The future therapeutic options for MS will depend on improvements in understanding the precise factors involved in disease onset and progression and subsequently the development of oral therapeutics that translate sustained benefit from the preclinical context into clinical reality.

Key Words: Multiple sclerosis; inflammation; demyelination; regeneration; experimental autoimmune encephalomyelitis; therapeutics

Article Outline

INTRODUCTION

EVALUATION OF CLINICAL OUTCOME IN MS

ANIMAL MODELS OF MS

CURRENT THERAPIES FOR MS

Corticosteroids

IFN-β

GA

EXAMPLES OF NOVEL THERAPEUTIC CHALLENGES FOR MS

Blockade of lymphocyte migration

Very late antigen-4: natalizumab (Tysabri) and small molecule antagonists.

Immunomodulatory agents

FTY720: sphinogosine-1 phosphate modulator.

Anti-inflammatory agents

COX-2 inhibitors.

Neuroprotective and neuroregenerative therapeutic strategies

Potential combinations of therapeutic strategies

FUTURE GOALS FOR DRUG DEVELOPMENT: TRANSLATIONAL SIGNIFICANCE

CONCLUSION

Acknowledgements

References

FIG. 1. Schematic view of the putative pathogenic steps in MS. 1: Activation of autoreactive T cells by antigen presenting cells in the periphery. 2: Migration of T cells and monocytes through the blood brain barrier. 3: Amplification of local inflammation and activation of resident microglia. 4: Release of toxic mediators damages myelin and oligodendrocytes with the culmination of axonal loss.

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Address correspondence and reprint requests to David J. Virley, Ph.D., Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom.

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