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Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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8

Recommendations

The ultimate goal of research in multiple sclerosis (MS) is the development of interventions that can improve the lives of those living with MS and prevent or cure MS. However, understanding of the MS disease process is not yet sufficient to predict which therapeutic strategies will be most effective. While the new disease-modifying drugs are a major leap forward, they are not a cure, nor are they effective for all patients. MS remains a mysterious disease with no known pathogen or even known determinants of its severity and course. Basic research provides a crucial foundation for innovative approaches to the discovery of effective therapies.

This chapter summarizes the recommendations that the committee believes have the greatest potential to facilitate broad advances in MS research. The committee was not asked to review specific programs of the National Multiple Sclerosis Society (the MS Society), but instead conducted its review more broadly to identify promising research strategies and opportunities for advancing MS research on a variety of fronts.

The committee did not suggest how the MS Society or others should prioritize the recommendations listed below. Prioritization of the recommendations requires programmatic decisions that will have to balance scientific opportunity with organizational goals. The choices, such as what balance to strike between patient services and research support, or between research on underlying disease mechanism and research to improve the lives of people with MS, go beyond strictly scientific questions and exceed the charge to the committee. Answers to those questions depend on the organization's mission and how it interprets that mission and should be determined by the directors, members, and constituents.

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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The committee feels that each of the research strategies listed below should be actively supported. However, which among them should take priority at any one time should be determined by a mix of scientific opportunity and institutional concerns, which will be different for different organizations, be they federal research sponsors or charitable health organizations. The most productive research strategies for an organization such as the MS Society will be influenced by the activities (or lack thereof) of the relevant federal agencies such as the National Institutes of Health, Agency for Healthcare Research and Quality, Veteran's Administration, and the National Institute on Disability and Rehabilitation Research, as well as those of other private organizations that sponsor research relevant to MS.

This chapter does not include numerous other committee recommendations that cover specific aspects of MS-related research, especially the recommendations dealing with specific symptoms or alternative medicine. These areas of research are covered individually in the pertinent chapters. The recommendations below are for research areas that the committee believes hold the greatest promise for developing treatments that can prevent or cure MS and for improving the lives of people with MS. They are organized into specific recommendations for the following:

  • research to understand the basic disease mechanisms, and specifically, the cellular and molecular events of MS;

  • tools for research and diagnosis;

  • research on new therapeutic approaches;

  • research toward improving the lives of people with MS; and

  • programs to promote progress in MS research.

ETIOLOGY AND PATHOGENESIS

RECOMMENDATION 1: Research on the pathological changes underlying the natural course of MS should be emphasized, because it provides the key to predicting disease course in individual patients, understanding the physiological basis of MS, and a basis for developing improved therapeutic approaches.

Unpredictability imposes a particularly acute burden on people with MS. They have no way of knowing when a relapse will occur, how impaired they will be, or whether they will recover from the relapse. Yet it is now clear that disease activity precedes relapses. Understanding these pathological changes is the first step toward predicting—at least in the short term—disease progression in individual patients.

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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Research on the natural course of MS would include defining the relationship between cellular and molecular changes and the progression of disability, as well as determining the physiological basis for different clinical manifestations of MS. Changes in gene expression should be analyzed in individual cell types, particularly those in and at the borders of lesions. Such information will also improve the ability to develop more refined diagnostic tools, provide benchmarks against which to measure the effect of therapeutic interventions, and provide the scientific basis for new therapeutic approaches.

Research on pathological changes occurring early in the disease should be particularly emphasized. This should also include the development of improved diagnostic criteria (most likely, criteria based on neuroimaging) that allow early and more accurate diagnosis of MS. If aggressive treatment is to be instituted at the onset of disease, early and accurate diagnosis is essential.

RECOMMENDATION 2: Research should be pursued to identify how neurons are damaged in MS, how this damage can be prevented, and how oligodendrocytes and astrocytes are involved in damage and repair processes.

Specific needs for research on neurons include the following:

  • investigations into the molecular pathophysiology of axonal injury in MS—what is the response of the neuronal cell body to demyelination and to degeneration of axons in MS?

  • delineation of the relationship of axonal injury to demyelination and inflammation, to the role of cytokines, and to the role of cell and antibody-mediated immune mechanisms;

  • delineation of the detailed nature of the secondary injury cascade that underlies calcium-mediated damage of axons within white matter;

  • improved understanding of the molecular mechanisms underlying restoration of conduction in demyelinated axons, with particular attention to identification of the sodium channel subtype(s) involved in conduction in chronically demyelinated axons, and identification and characterization of the promoter regions of the sodium channels that support impulse conduction in myelinated and demyelinated axons; and

  • identification of promoters and inhibitors of axon regeneration.

Specific needs for research on oligodendroctyes include identification of:

  • the role of oligodendrocytes in the trophic support of axons and neurons;

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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  • the role of oligodendrocytes in maintaining the distribution of sodium channels in axons;

  • the mechanisms that disable and destroy oligodendrocytes in MS;

  • how and to what extent progenitor cells are induced to become oligodendrocytes that remyelinate axons; and

  • the relationship between demyelination, injury to axons, and neuropathic pain in MS, and demyelination and axon injury in appropriate animal models.

Specific needs for research on astrocytes include the following:

  • Astrocytes as antigen-presenting cells. To what extent do astrocytes participate in the immunopathogenesis of MS? Is there an underlying disorder of astrocyte function in MS?

  • Astrocytes as producers of cytokines, chemokines or other molecules that influence blood-brain barrier permeability, immune cells, or myelin. Astrocyte response to neurotrophins should also be studied.

  • Astrocytes as scarring cells. Do scarring astrocytes inhibit remyelination or regeneration of axons in MS? If so, can this process be controlled?

  • Astrocytes as regulators of axonal conduction. The possible role of astrocytes as producers of sodium channels that are transferred to demyelinated axons should be explored.

  • Astrocytes as homeostatic regulators of the neuronal microenvironment. It is now well known that astrocytes can regulate the levels of biologically important ions, neurotransmitters, and related molecules in the healthy nervous system. Better understanding of this role of astrocytes in MS is needed.

Specific needs for research on interaction between neural and immune cells include:

  • more complete delineation of the mechanisms by which the immune system contributes to demyelination and remyelination;

  • interaction of T cells and antibodies with axons and neuron cell bodies;

  • identification of the humoral factors that increase the permeability of the blood-brain barrier, thereby allowing the trafficking of immune cells through the brain; and

  • evidence that immune cells destroy oligodendrocytes through the excita-

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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    tory amino acids acting through the AMPA/kainate receptors that are known to mediate cell death in a variety of circumstances should be clearly established and extended.

RECOMMENDATION 3: The genes that underlie genetic susceptibility to MS should be identified, because genetic information offers such a powerful tool to elucidate fundamental disease processes and prognosis, and to develop new therapeutic approaches.

Compelling data indicate that MS is a complex genetic disorder. The identification of susceptibility genes for MS represents a significant challenge but also a major opportunity to elucidate the fundamental disease process. Genetic discoveries are likely to contribute to a better understanding of heterogeneity, clinical course, prognosis, and response to therapy. Even the discovery of a new gene with a very small genetic effect on MS could have major implications for the development of entirely new therapies. The committee believes that an aggressive effort in human genetics is essential.

The critical importance of identifying rare families with monogenic variants of MS cannot be overstated; this approach has been extraordinarily fruitful in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

The following genetic research strategies should be emphasized:

  • The major histocompatibility complex (MHC) region in chromosome 6p21 should be targeted. The available data support the hypothesis that inherited susceptibility to MS involves the interaction of different susceptibility genes, each of which individually contributes to the overall risk. Whole-genome screens confirm the importance of the MHC genes in conferring susceptibility. Susceptibility is likely to be mediated by the MHC class II genes themselves (DR, DQ, or both) and is most likely related to the known function of these molecules in the normal immune response, antigen binding, and T-cell repertoire determination. The MHC region contains more than 250 genes, and despite the common assumption that DR2 is an MS susceptibility gene, because of marked linkage disequilibrium (or fixity of certain haplotypes) it has not been possible to determine with certainty which gene or genes are in fact responsible. The entire MHC region has now been sequenced, and it should be possible to better define the genetic role of the MHC in MS.

  • New statistical approaches should be developed to identify small genetic effects. Data show that although the MHC region contains significant susceptibility, much of the genetic effect in MS remains to be explained. It is likely that the non-MHC genes are all genes of small effect that contribute to susceptibility in an additive or synergistic fashion. In all

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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    likelihood, the use of phenotypic and demographic variables will assume increasing importance as stratifying elements for genetic studies of MS and as a means of addressing the fundamental question of genotype-phenotype correlation in autoimmune demyelination. These studies will necessarily be linked to the development of novel mathematical formulations designed to identify modest genetic effects, as well as interactions between multiple genes and interactions between genetic, clinical, and environmental factors.

  • Methods for rapid, high-throughput screening of genetic polymorphisms should be used. With the advances in deciphering the human genome code and sequences readily available in the public domain, future work should focus on the detailed analysis of candidate genes, in particular genes located in chromosomal segments linked to MS susceptibility or to susceptibility to demyelination in animal models.

  • “Case-control” population-based studies with limited statistical power should be replaced with the analysis of large collections. These collections should include nuclear or singleton families (the patient and the biological parents or the patient and healthy siblings) using transmission-disequilibrium tests (TDT) and Sib-TDT tests of association.

For complex disorders such as MS, genomic analysis of multiple candidate genes must be performed on an extremely large group of individuals if small genetic effects are to be detected. The key to the success of such studies will be the availability of rapid, reliable, non-labor-intensive methods for high-throughput polymorphism screening and a collaborative network.

  • Groups and consortia with the appropriate experimental, clinical, and financial resources should be supported to continue analysis of the MS genome. Larger DNA databases and dense and informative genetic markers—for example, single nucleotide polymorphisms (SNPs)—will be important to translate the basic understanding that genes are involved in MS into knowledge that can be used to facilitate the development of new therapeutic approaches and to provide more information for patients and physicians about risks associated with MS.

  • The inclusion of non-Caucasian patient populations, both in their native environment and after migration, will provide important new insights and clues about MS genetic and clinical heterogeneity. When MS occurs in non-Caucasians it is likely to provide more genetic information against a “non-MS” genetic background than against the Caucasian “MS-susceptible” background. Haplotypes of linked genes are often different in different ethnic or racial groups. When linkage studies identify a genetic region harboring an MS susceptibility gene, there are often 70

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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    to 100 genes within that region. Many of those genes are polymorphic, and common polymorphisms detected in different haplotypes and from different ethnic groups provide powerful clues to the location of the disease gene. Examples of genetically complex disorders in which this approach of transracial genotyping has been successful include narcolepsy and insulin-dependent diabetes mellitus.

  • Genomic, clinical, and endocrinologic information should be combined to investigate potential MS risk factors in large groups of female patients. Although sex differences in genetic susceptibility to MS have been well documented, rigorous studies assessing the potential role of sex-linked genetic factors in MS have not yet been performed. Further, changes in hormonal status associated with menstrual cycles, pregnancy, breastfeeding, and menopause might influence disease activity and should be investigated.

  • Studies should directly address the question of genetic heterogeneity in MS and the response to immunotherapy by analysis of the correlation between different genotypes and clinical response to therapeutic modalities (“pharmacogenomics”). A significant number of MS patients do not respond to the available disease-modifying treatments. Genetic polymorphisms in drug receptors, metabolizing enzymes, transporters, and targets have been linked to individual differences in the efficacy and toxicity of many medications.

RECOMMENDATION 4: Because the discovery of an MS pathogen would likely provide the single most important clue for identifying effective treatments, this search must remain a high priority, but should be conducted using powerful new and efficient methods.

Conventional tissue culture approaches to the isolation of pathogens in MS have consistently failed to find any convincing result, possibly because the pathogen does not grow in the tissue or media used. Newer approaches should be used, such as those that involve the identification of genomic information relevant to the pathogen and those that have the potential to reveal a broader range of pathogens than are detectable in culture. The methods include polymerase chain reaction (PCR), representational difference analysis, and sequence screening using the host immune response (described below). These powerful new methods have not yet been applied to investigations of MS tissues in any concerted and organized way, and their use should be a high priority.

Discovery of a trigger for the first MS event would likely provide the single most important clue for identifying a cure and a means of prevention. This event might precede clinically observable symptoms and might be different from the events that drive subsequent autoimmune attacks. Thus, despite the long and thus

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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far unsuccessful search, research to identify the trigger event(s) of MS must remain a high priority.

  • Representational difference analysis (RDA), one method of differential sequence analysis, has recently been used successfully to identify a new pathogenic herpesvirus in Kaposi's sarcoma. RDA employs PCR to amplify DNA fragments that are present in the diseased tissue, but not in healthy tissue from the same patient. The identification of even a small amount of sequence information may be sufficient to characterize the agent.

  • DNA microarrays, also known as DNA chips, can be used to reveal the coordinated expression of ensembles of critical genes. Different tissues can be probed to reveal which genes are activated by different candidate pathogens, or which genes are activated during tissue destruction or repair. This information will also provide important clues as to how these genes influence susceptibility and pathogenesis in MS. As gene chip methodologies mature, there is also the opportunity to perform wider whole-genome analyses of gene expression, unbiased by selection of known candidate genes.

  • Phage display libraries can be used to screen for the antigenic target of oligoclonal immunoglobulin G (IgG). The antigenic targets of the oligoclonal IgG might be a consequence of immunodysregulation rather than its cause, but knowledge of the target might guide the development of new therapies.

  • Other methods can be used to probe the antigenic targets of T cells that are present in the MS brain, although these results might be more difficult to interpret than when antibody is used.

RECOMMENDATION 5: Research to identify the cascade of immune system events that culminates in the destruction of myelin should remain a priority.

The most striking pathology in MS is the immune system's attack and destruction of the body's own myelin sheath. What causes the immune system to attack myelin is unknown. Although myelin basic protein (MBP) might trigger a particularly vigorous autoimmune response, it is not the only autoantigen, nor does it account for the full autoimmune response. Any brain protein is a potential autoantigen, although an autoimmune reaction to different proteins would have variable consequences. Two critical foci for research in the immunopathology of MS include:

    1. identification of the most important triggers for autoimmune responses in MS; and

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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    2. increased understanding of pathogenic immune cells.

One of the first pathological processes leading to MS attacks is thought to be activation of autoreactive T lymphocytes and their migration into the central nervous system (CNS) where they release cytokines that induce B cells to differentiate into antibody-secreting cells.2,3 However, T cells and the inflammatory molecules they secrete are not the only players. Many cells and molecules of the immune system—likely unleashed by T-cell activation—appear to participate in demyelination. The entire cascade of immune system events eventually culminates in myelin destruction. The key features of this cascade are not fully understood, including the precise ordering of events, the precise antigens targeted by T cells, and the precise contributions of B lymphocytes and other cells of the immune system.

Specific goals in research on pathogenic immune cells include the following:

  • identification of pathogenic T-cell clones using animal models that incorporate human-related genes and potential autoantigens and methods such as PCR, microarray assays, and phage display that do not rely on the ability of pathogens to grow in cell cultures;

  • characterization of the disappearance, reappearance, and persistence of autoreactive T lymphocytes over time;

  • identification of the blood-borne substances and cellular mediators that stimulate the migration of T cells and permit their passage across the blood-brain barrier and into the CNS; and

  • elucidation of the involvement of B cells in immune-mediated attack on the central nervous system.

TOOLS FOR RESEARCH AND DIAGNOSIS

RECOMMENDATION 6: The power of neuroimaging as a tool for basic research and for clinical assessment should be taken advantage of more extensively.

Neuroimaging is an invaluable adjunct to the history and clinical exam for evaluating the effects of therapeutic intervention. Research should emphasize the application of various accepted and evolving neuroimaging techniques to understanding the evolution of MS lesions from pre- or asymptomatic stages through the progression to permanent tissue alteration or recovery from disability.

Examples of the application of various techniques to understanding the MS disease process include the following:

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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  • magnetic transfer imaging (MTI), which provides an overall index of brain tissue destruction;

  • magnetic resonance spectroscopy (MRS), which provides an index of neuronal destruction, to study the evolution of early changes in normal-appearing white matter and to evaluate neurochemical change at various stages of the disease process;

  • gadolinium enhancement and contrast intensification of MRI to probe the evolution of inflammatory and blood-brain barrier changes;

  • diffusion tensor imaging, which can detect subtle pathological changes not apparent on conventional magnetic resonance imaging (MRI) and might thereby allow detection of pathological change in white matter tracts, including demyelination and loss of axons;

  • quantitative volumetric analyses of tissue destruction including the presence of “black holes” and atrophy;

  • functional MRI (fMRI) and positron emission tomography (PET) to evaluate changes in brain activity during active and recovering stages of MS and to analyze how these changes contribute to recovery; and

  • further development and validation of the use of spinal cord imaging to increase diagnostic sensitivity.

The committee also encourages the development of newer imaging modalities, such as:

  • high field-strength MRI to improve image resolution; and

  • specific labeling techniques that will allow the visualization of individual cellular populations (lymphocytes, glia, and specific neuronal populations) and processes (demyelination, remyelination, or neuroplastic changes).

RECOMMENDATION 7: Animal models should be developed that more faithfully mirror the features of MS and permit the analysis of how specific molecules and cells contribute to the disease process.

An animal model for a particular disease or condition can provide the understanding to design therapies based on biological knowledge, rather than shotgun testing. For example, mouse models with targeted mutations in the cystic fibrosis gene are providing a means for testing gene therapy delivered by aerosol into the lungs. Characterization of mouse models of various dwarfing syndromes, cloning of mutated genes, and parallel comparative genetic mapping and cloning of genes

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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for similar human syndromes have led to an understanding of various human dwarfing conditions.

Generation of a reliable animal model of MS has been a long-standing goal in MS research. Current animal models of MS express diseases like experimental allergic encephalomyelitis (EAE) or virus-induced demyelination. Although the models that are presently available have yielded a tremendous amount of information relevant to MS, better animal models can be developed. Key advantages of current animal models include the fact that the initiating trigger is known, the exact time of the initiating event is known, a great deal is known about the genetics and the immune system in the case of rodents, and finally, the availability of animal mutants with “knockouts” of genes for particular arms of the immune system or those that carry a transgene perturbing a protein that is relevant to MS.

A key disadvantage to available models is that they do not replicate the cellular or molecular pathology of MS. Some types of EAE, for example, produce brisk demyelination, whereas others produce little demyelination. In addition, these models are not very tractable for studies of the electrophysiology and biophysics of neuronal function, a serious limitation in a disease such as MS in which symptoms and signs arise from impaired nerve function.

Information gleaned from research studies of animal models could guide investigations into MS in the following ways:

  • Continued analysis of the genes responsible for different forms of demyelinating disease in experimental models such as EAE and Theiler's virus infection are likely to permit identification of the human chromosomal regions that contain the counterparts to these genes (syntenic regions). The possible role of the human genes in susceptibility to MS could then be probed.

  • Preclinical testing of CNS repair strategies (for example, cell transplant, growth factors, gene therapy) and optimal methods of CNS gene delivery can be carried out.

  • New methods for diagnosis of inflammatory demyelination, such as neuroimaging or spinal fluid evaluation, can be developed or refined in animal models.

  • Redundant EAE animal models can be developed that incorporate human-related genes and potential autoantigens, and new methodologies can be used to investigate animal models of MS. For example, investigations that involve mice with an inducible knockout of a specific arm of the immune system (for example, CD4+ T cells) may be of value. In the case of virus-induced demyelinating diseases, this approach will allow one to dissect the role of the immune system in virus clearance early after

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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    infection from its role in mediating the demyelinating disease late after infection.

  • Human virus-induced demyelinating disease and animal models of virus-induced demyelinating disease can be investigated for clues to the pathogenesis of MS. There are several advantages to investigating these disease processes: the initiating trigger for these diseases (that is, the virus infection) is known, and in many cases, the immune system appears to play a role in the pathology, as is the case with MS. In addition, a great deal is known about the immune system in rats and mice, and a wide variety of genetic models are readily available.

THERAPEUTICS

RECOMMENDATION 8: Strategies for protection and repair of neural cells, including the use of neuroprotective factors as well as stem cells, hold great promise for the treatment of MS and should be a major research priority.

Specific neuroprotective strategies to be investigated include:

  • elucidation of the pathways leading to cell death in the central nervous system;

  • identification of neuroprotective and repair strategies that will reduce or repair axonal injury;

  • development of therapeutic approaches that will induce restoration of conduction in demyelinated axons, for example, by inducing expression of appropriate densities of the appropriate subtype(s) of sodium channels among them;

  • development of approaches to stimulate re-growth of damaged axons; and

  • development of systems for the delivery of neuroprotective and repair factors to the central nervous system.

An effective delivery system is an essential link in the development of neuroprotective or restorative therapies. Thus, the development of such delivery tools, for example, cells that have been genetically engineered to produce specific neuroprotective factors, or molecular packaging systems, is a high priority.

Specific goals to identify the cellular and molecular pathways that control the death of myelin-forming oligodendrocytes include identification of the following:

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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  • therapeutic strategies that can protect oligodendrocytes from immune attack;

  • strategies to activate endogenous oligodendrocyte precursor cells to promote remyelination (endogenous stem cells); and

  • strategies for the transplantation of myelin-forming cells into the demyelinated CNS; this includes using precursor cells or genetically engineered cells (exogenous stem cells).

The last two strategies must be considered in the context of specific features of MS. For example, newly formed myelin might be destroyed through the same immune response that destroyed the original myelin.

RECOMMENDATION 9: New, more effective therapeutic approaches to symptom management should be pursued, including those directed at neuropathic pain and sensory disturbances.

  • The pathophysiology of pain and paresthesia in MS is not understood. Although neuronal hyperexcitability appears to underlie these symptoms, it is not known why it occurs in MS. The cellular and molecular basis for neuronal hyperexcitability in MS should be investigated.

  • Molecular targets should be identified, for example, inappropriately expressed ion channels that cause abnormal impulse trafficking in MS. After identification of such targets, pharmacological methods can be developed for regulating the activity of these critical molecules.

  • The impact of electrical activity within neurons and of exercise and physical therapy should be investigated in regard to disease progression and functional capacities. This will require the development of better tools to measure function.

RECOMMENDATION 10: In the absence of any fully effective therapies, integrated approaches for the delivery of currently available therapeutic agents should be investigated.

Since there are, as yet, no treatments that cure MS or halt disease progression entirely, it is important to develop integrated approaches to testing those agents that can at least modify the course of the disease. Such trials are expensive and lengthy, and they require large numbers of patients. Agents of different classes will have to be tested in sequence and in combination. Such trials are also best done when the dose range and safety profile of each individual agent to be employed in the trial are known, and the potential for adverse drug interactions should be carefully monitored. Separate end points might be required for each agent as appropriate to its individual pharmacological profile. Most importantly, standardized protocols and assessments will have to be devised and agreed upon,

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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including Phase II studies that will allow abandonment of ineffective combinations before incurring the time, expense, and exposure to risk that are inherent in large, multicenter efficacy trials.

Specific considerations include:

    1. timing of initiation of treatment in regard to clinical course;

    2. use of combination regimens:

    • appropriate dosing of single agents;

    • use of appropriate combinations, such as interferon and glatiramer acetate, and interferon and cytostatic drugs;

    • use of chemotherapy regimens as a model approach; and

    • sequencing or cycling of different agents; and

    3. improved classification of disease stage to permit the selection of agents or combinations of agents that are most appropriate for each disease stage.

RECOMMENDATION 11: Better strategies should be developed to extract the maximum possible scientific value from MS clinical trials.

The committee noted that many of the pivotal MS clinical trials on disease-modifying therapies were terminated early, usually because of predetermined stopping rules and, thereby, unique opportunities to obtain critical data were lost. The MS Trials Research and Resource Center that is being organized by the International Federation of MS Societies* is an example of the sort of project that should increase the potential scientific value of MS clinical trials.

Other suggestions for increasing the efficiency of clinical trials include the following:

  • Alternatives to placebo-controlled studies should be investigated. Despite their scientific power, randomized placebo-controlled clinical trials are not always practical or ethical. Withholding effective treatment from a patient enrolled in the placebo arm of a clinical trial could be unethical.

  • Clinical trials should be designed in close collaboration with immunologists, virologists, geneticists, and neuroimaging experts.

  • Clinical research in MS should move toward adopting the inclusion of a brief and concise measure of health status. Such a measure not only


*In January 2001, the name was changed to Multiple Sclerosis International Federation.
Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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    would provide a direct measure of health outcome, but also would increase the likelihood of detecting unanticipated side effects.

  • A data registry of patients taking disease-modifying drugs should be established that would allow for the detection of long-term effects and provide the basis for an understanding of individual variations in response to those therapies. The data should include neuroimaging-based information and should be accessible for reanalysis as a baseline for serial studies. At the same time, the confidentiality of individual patient records must be protected.

  • The number of patients available for clinical trials is limited and should be managed in an organized fashion. As increasing numbers of early-stage patients are on disease-modifying therapies (beta-interferons or glatiramer acetate), increasingly fewer will be available for clinical trials that rely on previously untreated patients.

HEALTH STATUS AND QUALITY OF LIFE

RECOMMENDATION 12: Health status assessment methods for people with MS should be further developed and validated to increase the reliability and power of clinical trials and to improve individual patient care.

Quantifying health status, including functional status and quality of life, for persons with MS is essential for several reasons. Given the chronicity and uncertain course of MS, tracking its impact over time can assist with care of individual patients by suggesting near-term prognoses and the need for various interventions. Tabulating these findings across individuals offers insight into the burden of MS-related disability within populations, information increasingly used to set research, health, and social policy priorities. Longitudinal studies of the trajectory of functioning and quality of life should help to define the natural history of the disease and expand understanding of the variations in its clinical course and patterns of progression. Finally, functional status and quality of life are critical end points in measuring the effectiveness of therapy, both for clinical trials and for routine patient care.

Clinical neurology should move toward adopting as a standard of care a concise measurement of health status that includes quality-of-life measures, as well as impairment and disability measures. This could serve as the basis for communication between physicians and other caregivers and for increasing the efficiency and thoroughness of consultations between patients and physicians, particularly if filled out by patients before meeting with the physician. If long-term records of such data were maintained in a data registry, they would also

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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provide much needed insights into the natural course of the illness. Individual records would provide information about patient health that would not normally be collected in a routine clinical exam.

The development and validation of new impairment and disability measures should continue to be supported. Validation of the MS Functional Composite Scale should continue, particularly to measure its sensitivity to changes in patient condition over time.

RECOMMENDATION 13: Research strategies aimed at improving the ability of people with MS to adapt and function should be developed in partnership with research practitioners, managers, and patients; toward this end, a series of forums to identify the most pressing needs experienced by people with MS should be convened.

The goal of such forums would be to define research needed to identify ways to help people with MS adapt to their illness and enhance their ability to function. There is such a small body of empirical research on this topic that the committee was not able to specify the most appropriate research strategies. Rather, the committee recommends that the MS Society work in partnership with people with MS to guide the development of specific research strategies that will identify the most effective approaches toward improving their everyday lives. A series of forums could provide the needed perspective to defining those research strategies and should include the following constituencies:

  • patients and their families;

  • health care providers;

  • allied heath professionals, such as physical therapists, occupational therapists, and social workers;

  • health services researchers, including survey scientists and clinical epidemiologists;

  • social scientists, including sociologists, anthropologists, and psychologists; and

  • representatives of organizations of patients with other disorders that present some of the same challenges faced by people with MS.

Specific individuals should be identified, including those whose work focuses on related issues outside the field of MS. Since the research community that deals with these issues is small and has so many fewer funding resources than biomedicine, it is essential to look more broadly for resources. The needs of people with other chronic, debilitating diseases have much in common with those of people with MS. The MS Society might work with other relevant societies and

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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government funding agencies to identify the most important research questions with the goal of improving the lives of people with chronic and debilitating diseases.

New strategies are needed to improve dissemination of the latest research information and to develop the best methods of informing patients so they can take full advantage of treatment options and available assistance. This includes developing a better understanding of the most effective timing, settings, and modes of delivering information. Some information is important to deliver at the time of diagnosis (for example what to expect in the next few years, how to ensure health care); other information is only of interest to patients much later in the disease course (for example, how to obtain and choose a wheelchair). How, when, and where information is communicated needs to be considered. Certain information is best imparted by a health care provider during a private, scheduled visit; other information is best gained in a group setting. Some information has to be processed and molded to fit individual needs, and this is often accomplished more effectively in the back-and-forth exchange of a group setting. Uses of computers, including the Internet and chat groups, should be researched.

Specific research needs include:

  • research to better understand the best approaches to making decisions about patient care in the face of uncertainty, with emphasis on addressing needs expressed by the patient;

  • research on ways to help people with MS adapt to the illness and enhance ability to function;

  • research to define the optimal models of care at different disease stages— this should include the impact of managed health care and policies of national health care plans; and

  • research to define protocols for appropriate health care referrals. These should be useful for all health care providers, but especially primary care physicians and nurses who are not MS specialists and who would benefit from guidance about when to refer patients to occupational or physical therapy or when to recommend assistive technology.

RESEARCH ENTERPRISE

In order to stimulate and support MS research, there is a need to broaden the community of MS researchers, to recruit more neuroscientists to MS research, and to increase exchange between clinical and basic MS researchers. New approaches gained from outside the realm of the MS scientific community are worth considering.

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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RECOMMENDATION 14: New researchers should be actively recruited to work in MS, and training programs should be designed to foster productive interactions with established investigators both within and outside the MS research community.

MS defies disciplinary boundaries. Understanding the biological mechanisms that underlie the disease and developing effective therapies rest on contributions from immunology, microbiology, genetics, genomics, neuroscience, and other fields. For instance, any therapies directed at neural repair will be effective only if they are not thwarted by the underlying immune-mediated attack. Conversely, while immune-based therapies might slow or halt the further advance of disease, they are relatively unlikely to offer much in terms of repair. Even if all demyelinating attacks could be stopped overnight, there are still thousands of people with MS who could potentially benefit from neural repair therapies.

In the last few decades there has been a tremendous influx of talented researchers into the field of neuroscience. Yet committee members observed that this burgeoning pool of researchers has not been drawn to MS research in the same numbers as they have to other neurological diseases. Contemporary neuroscientists bring an appreciation of nervous system functioning across the breadth of cell and molecular biology, and the committee feels that specific efforts should be made to encourage greater integration of neuroscience researchers into the multidisciplinary MS research community.

To bring new researchers into MS, it is not enough to rely on people who have already shown an interest in it. Active outreach is necessary. Promising researchers from all relevant disciplines should be sought and encouraged to participate in the fight against MS. Funding new researchers is of little value without the ability to sustain the investment. Attracting new researchers should be balanced with reasonable expectations that successful researchers can continue. In the 1990s, more Ph.D.s were awarded than could be employed in research. During such periods, recruitment efforts by private research foundations might be more productive if they were to shift the balance of their recruitment efforts toward reducing support for training Ph.D. students and increasing support for postdoctoral fellows.

RECOMMENDATION 15: Concerted efforts should be made to stimulate enduring interdisciplinary collaborations among researchers in the biological and non-biological sciences relevant to MS and to recruit researchers from other fields into MS research.

Concerted efforts should be made to stimulate enduring cross-pollination among researchers in the biological and non-biological sciences. It is not enough to bring in researchers from other fields to participate in isolated workshops. While this can provide fruitful injection of new ideas, it does not go far enough to ensure cross-pollination. Sustained interactions that promote productive collaborations or the development of new ideas need to be fostered.

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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The committee felt that giving a small amount of funding (for example, $100,000) to an established laboratory, which has been done in the past, is not enough to encourage researchers to pursue MS research. Programs to encourage cross-pollination should be proactive. Individual researchers should be targeted. This has been tried successfully by a number of other private health foundations (for example, the Hereditary Disease Foundation, CaP CURE, and the Amyotrophic Lateral Sclerosis Association).

There is still too little cross-talk between clinical and basic scientists. One means of stimulating more exchange between basic researchers and clinicians would be to provide funding for minisabbaticals in which basic scientists could work with clinicians for one- to two-month visits. Although there are many researchers who combine skills in clinical and basic science, there is a major need for basic scientists, particularly in the neurosciences, who have an interest in pursuing MS research. This should be actively encouraged by organizing symposia at scientific meetings, such as those of the Society for Neuroscience, where MS research has received relatively little attention.

RECOMMENDATION 16: Programs to increase research efficiency should be developed, including collaborations to enable expensive large-scale projects (for example, clinical trials, genome screens) and to organize collection of scarce resources (for example, human tissue).

The committee recommends that MS societies consider exploring less conventional approaches such as those tried by other health care foundations. The societies should consider leading an effort to identify and develop successful models of collaboration. Although the MS societies cannot fund many clinical trials, they might be able to work as a catalyst to facilitate more effective, far-reaching clinical trials, for example, by bringing together the right people.

This would also include the development of data registries that would apply to natural history studies and long-term therapeutic evaluations.

RECOMMENDATION 17: New strategies should be developed to encourage more integration among the different disciplines that support and conduct research relevant to improving the quality of life for people with MS.

This would include research on the instruments used to assess quality of life, employment issues, personal independence, and the identification of optimal models of caring for people with MS. Research in these areas has too often proceeded in parallel paths with little apparent recognition of the work of others. For example, many articles about the psychosocial aspects of MS are published in nursing, psychology, physiotherapy, and neurology journals, and yet they often fail to cite articles on the same topic published outside their professional disciplines.

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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Because the health policy research field is relatively small and research funds are limited, partnerships should be developed among MS societies and other voluntary health research organizations supporting research on diseases that confront patients with similar challenges. Although each of these diseases has some unique features, for the most part, the research techniques, patients' needs, and even the investigators themselves overlap across different diseases, particularly chronic, debilitating diseases. Examples of such diseases include rheumatoid arthritis, diabetes, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Much of the research on quality-of-life issues for any of these diseases is likely to be relevant to people with MS. Indeed the development of partnerships among the related health care organizations should benefit a far greater number of patients than each could serve alone. Partnerships could take a variety of forms from collaborative development and funding of requests for proposals (RFPs) to collaborations in convening symposia and workshops.

The committee does not believe that research in health care is optimally served by contracts. However, in recent years, the National MS Society has emphasized the use of contracts for directed research in health care, a strategy it adopted in response to the generally poor quality of the grant applications they had received in past years. While contracts can provide for the collection of useful data, they also bypass the greatest source of creativity—the individual investigator. Committee members noted that otherwise qualified people have chosen not to apply because they find the contracts intellectually confining or conceptually incompatible with their perspectives. Thus, the most innovative researchers might be the least likely to apply, which is troubling since the pool of qualified applicants is already small compared to biomedical researchers. The committee endorses the 2000 decision of the Health Care Delivery and Policy Research Committee of the National MS Society to adopt a more open framework allowing potential applicants more latitude to propose their own ideas. This represents a middle-ground between targeted research and open-ended investigator-initiated proposals.

RECOMMENDATION 18: To protect against investing research resources on false leads, there should be an organizational structure to promote efficient testing of new claims for MS pathogens and disease markers.

Over the years, various viruses, bacteria, and toxins have been proposed as possible causes of MS. None of them have withstood the scrutiny of careful research, although, in a few cases, they have not been ruled out as causes. Although erroneous claims in MS research are relatively rare—there have been fewer than five in the last five years—their effects can be far-reaching. In some cases, erroneous claims have misdirected research, resulting in a substantial but unproductive investment in time and money. These erroneous claims have also

Suggested Citation:"8 Recommendations." Institute of Medicine. 2001. Multiple Sclerosis: Current Status and Strategies for the Future. Washington, DC: The National Academies Press. doi: 10.17226/10031.
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led to the treatment of patients with inappropriate, expensive, and potentially harmful therapies. For example, the claim that metal toxicity causes MS induced some patients to have teeth extracted and amalgam fillings removed. New claims of MS pathogens, when appropriate, should be resolved as quickly as possible.

The MS societies are the most likely organizations to undertake efforts to test the validity of a newly proposed pathogen on an ad hoc basis. Following a potentially credible claim implicating a particular pathogen in MS, the society could oversee a project whereby the investigator making the claim, as well as an expert in the particular pathogen, could review clinical samples. A similar approach could be made in response to other claims related to the diagnosis or the treatment of MS in situations in which a quick confirmation of the results would be of importance to MS patients or the neurological and scientific communities. This approach should reduce costs to patients, researchers, and even the MS Society. The key elements of such a program would be evaluation of credible claims that are judged to have the potential for influencing research strategies or treatments, rapid response, and the generation of replicate data sets necessary to establish reliability of claims.

If the validation experiments were conducted in established laboratories equipped with the necessary expertise and research tools, the costs should be relatively low. These could be supported by a direct payment or small grant supplement provided in advance to investigators who agree to participate in such a program. It might also be possible to offer the possibility of confirming such path-breaking claims prior to their initial publication in order to increase the immediate impact of the discoveries or spare investigators embarrassment should their data be incorrect.

The Amyotrophic Lateral Sclerosis Association has recently tried such an approach in response to a report of enteroviral RNA found in gray matter tissue of the spinal cord of patients with ALS.1 The association provided funds to the author of that paper to replicate the study and expand it. The same blinded samples will also be sent to the Enterovirus Section of the National Center for Infectious Diseases, part of the Centers for Disease Control and Prevention, for independent verification.

REFERENCES

1. Berger MM, Kopp N, Vital C, Redl B, Aymard M, Lina B. 2000. Detection and cellular localization of entero virus RNA sequences in spinal cord of patients with ALS. Neurology.; 54: 20-5.

2. Hohlfeld R. 1999. Therapeutic strategies in multiple sclerosis. I. Immunotherapy. Philos Trans R Soc Lond B Biol Sci.; 354: 1697-710.

3. Lassmann H. 1999. The pathology of multiple sclerosis and its evolution. Philos Trans R Soc Lond B Biol Sci.; 354: 1635-40.

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Multiple Sclerosis: Current Status and Strategies for the Future Get This Book
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Multiple sclerosis is a chronic and often disabling disease of the nervous system, affecting about 1 million people worldwide. Even though it has been known for over a hundred years, no cause or cure has yet been discovered—but now there is hope. New therapies have been shown to slow the disease progress in some patients, and the pace of discoveries about the cellular machinery of the brain and spinal cord has accelerated.

This book presents a comprehensive overview of multiple sclerosis today, as researchers seek to understand its processes, develop therapies that will slow or halt the disease and perhaps repair damage, offer relief for specific symptoms, and improve the abilities of MS patients to function in their daily lives.

The panel reviews existing knowledge and identifies key research questions, focusing on:

  • Research strategies that have the greatest potential to understand the biological mechanisms of recovery and to translate findings into specific strategies for therapy.
  • How people adapt to MS and the research needed to improve the lives of people with MS.
  • Management of disease symptoms (cognitive impairment, depression, spasticity, vision problems, and others).

The committee also discusses ways to build and financially support the MS research enterprise, including a look at challenges inherent in designing clinical trials. This book will be important to MS researchers, research funders, health care advocates for MS research and treatment, and interested patients and their families.

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