Multiple Sclerosis Therapeutics PDF

Preface to third edition

Our understanding and treatment of disease at any point in time is largely governed by the state of the known technologies at the time. New technologies are usually quickly applied to the study of diseases and their therapies. Since publication of the 2nd edition of Multiple Sclerosis Therapeutics, the advances of the Human Genome Project, newer molecular biology techniques (such as the use of small interfering RNAs for knocking down gene expression and improved abilities to induce expression of genes of interest in vivo and in vitro) and improved cell culture techniques have identified new therapeutic targets for the immune-mediated aspects of multiple sclerosis (MS) disease and provided new insights into neuroprotection and neuroregeneration. New cell types identified in the immune system, such as regulatory T cells and subsets of dendritic cells, provide new options for devising immune-based therapies. Advanced imaging techniques are telling us more about the pathogenesis and heterogeneity of disease.

Since the previous edition of this book, there has been substantial progress in a number of areas. Although immunosuppressive treatments continue to be developed and refined, more targeted immunomodulatory therapies are surfacing as we learn more about how the immune system works in health and disease. For example, adhesion molecules such as those in the integrin family have been targeted, with impressive therapeutic results but, in the case of natalizumab, with the unusually specific, although uncommon, development of progressive multifocal leukoencephalopathy. Other molecules involved in the circulation of immune cells (e.g. the sphingosine-1-phosphate receptor and chemokines) are also the subject of therapies in the pipeline. There has been increased appreciation of humoral immune mechanisms in MS, leading to clinical trials of agents directed against these features. The somewhat surprising anti-inflammatory properties of the statin drugs, previously developed to improve one's lipid profile, have led to clinical trials in autoimmune disease, including MS. The identification of biomarkers for the presence of disease, or for the level of disease activity, is leading not only to new therapeutic targets but also to new methods for monitoring the effects of therapy. An improved understanding of the downstream effects of current immunomodulatory therapies, particularly on levels of gene expression within the immune system, is showing promise for the ability to predict whether an individual will be a responder or non-responder to a given therapy. Similarly, the relatively nascent field of pharmacogenomics may allow the sophisticated prediction of either efficacy or tolerability of specific drugs in individuals.

Our level of sophistication regarding clinical trial design has also continued to evolve, thanks in large part to the work of the National Multiple Sclerosis Society's Advisory Committee on Clinical Trials. Their work has improved our understanding and use of outcome measures, including surrogate markers whose eventual use will facilitate and speed up our clinical trial process. Imaging modalities that continue to be evaluated, or are being newly evaluated, include magnetization transfer imaging, diffusion tensor imaging, magnetic resonance spectroscopy, functional magnetic resonance imaging and optical coherence tomography. Improved imaging of the spinal cord remains an important technical goal. The Committee continues to tackle the difficult issue of how to evaluate, as outcome measures, symptoms that are predominantly subjective in nature, such as pain and fatigue.

New understanding of the natural mechanisms that prevent central nervous system (CNS) regeneration are propelling us toward the next frontier, the repair of the CNS and reversal of long-standing deficits secondary to CNS damage. Recent increases in our knowledge of the neuropathology of MS make it clear that both remyelination and axonal repair will be necessary to fully achieve this goal. What sounded like science-fiction a few short years ago now appears approachable. As our ability to control the inflammatory, demyelinating phases of the disease becomes more complete, and as we learn more about neuroprotection, the feasibility of tackling the repair issue comes closer to reality. Within the next several years we will begin to discover the utility and the limitations of stem cells in the treatment of MS. It is likely that the 4th or 5th edition of Multiple Sclerosis Therapeutics will begin to include clinical trial data that evaluate early attempts at nervous system regeneration in MS. The methodological and technological advances that will evolve over the next decade can only be guessed at today, but it is certain that MS investigators will continue to apply them to the treatment of this disease until it is solved.