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6

Future Strategies for MS Therapies

This chapter focuses on the development of therapies that can halt or slow the disease process in multiple sclerosis (MS). Therapies for the relief of specific symptoms are discussed in Chapter 3.

The plethora of potential therapeutic agents and the multiplicity of patterns and stages of disease to which each might be applied will demand tailoring of pivotal clinical trial designs to the specific clinical situation. Such tailoring will involve trial duration, selection of outcome measures, and as a consequence, sample size.

Modification of the course of MS presents opportunities for five types of interventions:

    1. Primary prophylaxis in at-risk individuals. These trials will be aimed at preventing the appearance of overt disease in two populations of patients: (1) individuals who have presented clinically with an episode of monosymptomatic demyelinating disease and (2) individuals known to be genetically at risk.

    2. Relapse prevention via immune modulation. In this category, one would place the recent and ongoing trials of the beta-interferons—those whose primary clinical targets were relapse rate, with secondary outcome measures of magnetic resonance imaging (MRI) progression. In these studies, the interferons, all to a similar degree, decreased relapse rates as well as the number of gadolinium-enhancing lesions. However, glatiramer acetate reduced clinical activity to a similar degree without as profound an effect on the MRI. Thus, different agents might produce similar clinical



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Page 277 6 Future Strategies for MS Therapies This chapter focuses on the development of therapies that can halt or slow the disease process in multiple sclerosis (MS). Therapies for the relief of specific symptoms are discussed in Chapter 3. The plethora of potential therapeutic agents and the multiplicity of patterns and stages of disease to which each might be applied will demand tailoring of pivotal clinical trial designs to the specific clinical situation. Such tailoring will involve trial duration, selection of outcome measures, and as a consequence, sample size. Modification of the course of MS presents opportunities for five types of interventions: 1. Primary prophylaxis in at-risk individuals. These trials will be aimed at preventing the appearance of overt disease in two populations of patients: (1) individuals who have presented clinically with an episode of monosymptomatic demyelinating disease and (2) individuals known to be genetically at risk. 2. Relapse prevention via immune modulation. In this category, one would place the recent and ongoing trials of the beta-interferons—those whose primary clinical targets were relapse rate, with secondary outcome measures of magnetic resonance imaging (MRI) progression. In these studies, the interferons, all to a similar degree, decreased relapse rates as well as the number of gadolinium-enhancing lesions. However, glatiramer acetate reduced clinical activity to a similar degree without as profound an effect on the MRI. Thus, different agents might produce similar clinical

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Page 278 results, but with different imaging profiles because each targets a slightly different aspect of the underlying disease pathology. 3. Relapse limiting. Current practice is to treat acute relapses with intravenous methylprednisolone. However, no criteria have been adopted that permit uniform designation of the onset and completion of a relapse. The difficulty in this area arises from the fact that relapses can take numerous forms, from monosymptomatic optic neuritis to acute transverse myelitis, and so forth. Nonetheless, if treatments are to be tested for the ability to shorten individual relapses, then criteria for determining precise clinical onset and end of relapse episodes will be required. 4. Progression altering. To date, clinical measures of progression of disability have correlated poorly with imaging measures in MS clinical trials. The exception appears to be the estimation of brain atrophy. Studies evaluating the effects of agents on disease progression will have to incorporate measures of brain and spinal cord parenchymal volume as well as more sensitive and reproducible measures of neurological function than those currently in use. 5. Neuroprotective and restorative. Chapter 5 discusses the potential of and rationale for the use of various neuroprotective and potentially restorative therapies for MS. Many of the current putative neuroprotective or restorative agents in clinical or pre-clinical research are protein growth factors that must somehow be delivered to the central nervous system (CNS), either directly or across the normally restrictive blood-brain barrier. However, it should be noted that insulin-like growth factor-1 (IGF-1) appears to cross the blood-brain barrier in certain experimental autoimmune encephalomyelitis (EAE) models, so the inflammatory nature of the acute MS lesion might permit the use of such agents in the acute setting. Designs for trials of neuroprotective or glioprotective agents in MS will depend on the nature of the question being asked, as well as the specificities and properties of the agent being tested. STRATEGIES FOR DISEASE MODIFICATION Advances in understanding the molecular neurobiology of myelinated axons, as described in Chapter 2, have revealed much about the contribution of impaired impulse conduction to symptom production in MS. Nonetheless, there is much more to learn about the mechanisms underlying demyelination and axonal injury in MS. What are the precise molecular steps that lead from the initial immunologic assault to the death of oligodendrocytes and the degeneration of axons? Are there steps at which these cascades can be halted? It has recently been suggested that cytokines might play a role in injuring myelinated nerve fibers in MS. More information is needed about which cytokines are involved and which molecular

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Page 279pathways carry out their injurious actions. Cytokines and the toxic levels of nitric oxide (NO) that they produce can be manipulated in a variety of ways and could provide a target for therapeutic interventions in demyelinating disorders. Immune-Based Therapy Antigen-specific tolerance, a method of antigen-specific immunomodulation, relies on administering an MS-related antigen in a manner that induces tolerance, thereby reducing the immune response to that antigen. Myelin basic protein (MBP) acts as a classical encephalitogenic autoantigen in certain EAE models, which has raised hopes for the development of T-cell-based therapies in which MS patients could be vaccinated with targeted portions of the MBP molecule to induce tolerance and prevent further T-cell-mediated attack. However, as reviewed in the “Immunopathology” section of Chapter 2, the human response to MBP is more complex than that in these EAE models. Indeed, MBP does not act as a classic autoantigen in humans, and even among EAE models, it is highly variable. Generally, it appears that the T-cell response against myelin proteins also differs greatly between individual patients, suggesting that immune therapies might have to be individually tailored for different patients. Another concern of this approach is that the immune response to antigen administration follows an unusual dose-response curve. Although low-dose administration of most drugs is generally the safest course when beginning clinical trials, low-dose administration of antigen can, in fact, sometimes induce unsafe immune responses, whereas high doses can induce tolerance. Vaccination Vaccination, of course, would be an attractive therapeutic avenue. In fact, numerous variants of vaccination have been proposed. These include vaccination with whole myelin-specific T cells,8,33 with T-cell receptor peptides,13,107,116 DNA-encoding autoantigens, or T-cell receptor (TCR) sequences.64,111 Some of these therapies were quite impressive in EAE models when immunization was induced against a known target autoantigen (for example, MBP, MOG, or PLP), but at least in the case of TCR vaccination, the therapy failed in human MS. This is already an active area of corporate research, which has thus far has not fulfilled our hopes. Although potentially of significant therapeutic value, the induction of tolerance remains poorly understood, making it difficult to test clinically. Suppressor Cells For the most part, T cells are considered to underlie the immune-mediated attack on myelin, but one class of T cells—suppressor cells—can suppress the activity of pathogenic T cells and might play a protective role in MS.57 Several

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Page 280types of cells, including CD4 minus and CD8 minus positive suppressor cells have been shown to suppress EAE in some animal models, but the role of suppressor T cells and their potential for therapeutic use in MS are far from clear. CD25+ T cells are closest to the classic suppressor cells, but they are enigmatic and not well characterized in terms of antigen specificity, function, and mechanism of action. Their existence has been postulated on the basis of transfer and depletion studies in vivo (Don Mason, Ethan Shevach), as in the NOD mouse model of insulin-dependent diabetes mellitus (IDDM), in neonatal thymectomy models of multiorgan infiltration (Sakaguchi), and also in T-cell receptor transgenic, “monoclonal” mice (Tonegawa; Lafaille). Evidence for a role of these cells in CNS-specific autoimmune diseases is indirect at best. Immunodeviation Approach potential involves inducing immunodeviation of myelin-specific T cells, that is, shifting the balance of production from Th1 to Th2 cells. This is a crowded field in MS research, as in other putative autoimmune diseases. Several private firms are investigating this strategy, and the committee feels this approach is already receiving adequate attention and is not lacking for encouragement. Further, in the pathogenesis of EAE and MS, there is no clear distinction between “good” Th2 and “bad” Th1 T cells. Both cell types might produce pathogenic inflammation in different situations. Genetic Engineering Another possible innovative therapy would be to use genetically engineered autoimmune T cells. Even though the precise pathological roles of T cells and their autoantigens are unresolved, this line of research has generated many approved or emerging therapies. These include vaccination strategies, which use either attenuated myelin-specific T cells97,33 or peptides representing myelin-specific T-cell receptors3 as vaccines to strengthen the body's own regulatory responses against pathogenic T cells (reviewed in 1998 by Zhang et al.).120 Also under development are “altered peptide” therapies that use peptide analogues of myelin protein segments to induce autoreactive T cells to produce protective, rather than pathogenic, cytokine mediators.96 Neuroprotection Recent studies have elegantly demonstrated the loss of axons in chronic MS lesions. As discussed elsewhere in this report, the precise mechanisms leading to axonal degeneration in MS are at present unknown. Axons can degenerate as a result of the loss of trophic support of their myelin sheaths. Alternatively, they

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Page 281can be victimized as “innocent bystanders” in the surrounding inflammatory milieu. In addition to the structural loss of axons in MS lesions, axonal dysfunction and conduction block in demyelinated foci also contribute to neurological symptoms in MS patients. Axonal loss occurs early in disease and is possibly the major cause of irreversible neurological impairment.104 Neuroimaging studies suggest that axonal loss begins as early as the onset of disease. Axonal damage leads to Wallerian degeneration and the loss of neuronal cell bodies. MRI and computed tomography (CT) scans of MS victims show evidence of widespread atrophy. It is unclear at present whether the loss of axons leads to neuronal cell death in MS. However, accumulated axonal loss and dysfunction, especially in the progressive phase of the disease, underlie the progressive neurodegeneration seen in MS. Thus, therapeutic strategies aimed at preventing neuronal damage might be a key to preventing permanent disability. There are a variety of approaches to anti-inflammatory strategies, remyelination, and the use of specific neuroprotective agents, and these are considered in turn below. Anti-inflammatory Strategies The most obvious “neuroprotective” strategy for the treatment of MS is prevention of the inflammatory lesion that leads to demyelination and oligodendrocyte loss. Anti-inflammatory approaches are discussed elsewhere in this volume. However, it should be noted that in the course of inflammation, cytokines such as tumor necrosis factor-α (TNF-α) and lymphotoxin are produced, and they can be damaging to neurons and glia. Furthermore, the reactive oxygen species, nitrous oxide and glutamate, produced by invading inflammatory cells can be toxic to both oligodendroglia and axons that pass through regions of active demyelination. Therapies aimed at preventing oxidative damage to neurons might, therefore, be effective in minimizing neurological impairment during acute MS attacks. Remyelination Trophic and other interactions between axons and ensheathing glial cells contribute to the structural and functional integrity of axons. Therefore, administration of agents that promote remyelination or ameliorate damage to myelin should also protect neurons. Such strategies might include administration of gliotrophic factors or transplantation of glial precursors or stem cells that repopulate demyelinated regions of the CNS.112 Attempts at myelination occur in and around MS lesions.54,85,92 Especially in recent lesions, an abundance of oligodendrocytes may be found, as well as axons with thin myelin coatings and shortened internodes. This presumably indicates de novo myelin formation as it does in remyelination of peripheral nerves. Lassmann

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Page 282and colleagues have categorized MS lesions into five types, based on the degree of oligodendrocyte destruction and the stage of apparent repair.54 Having noted that attempts at myelin repair are not uncommonly found in MS brains, it may be assumed that at some level, this phenomenon is responsible to greater or lesser degree for the recovery of function that occurs after relapses. Thus, the time course and the degree of recovery from individual bouts of demyelination give us some notion of the capacity of the CNS to repair myelin damage. The obvious questions then are why remyelination and recovery are not universal, what factors inhibit remyelination, and what therapeutic options might exist to promote remyelination in the future? The cell type responsible for initiating the process of remyelination in MS plaques is at present unknown. Mature oligodendrocytes are incapable of mitosis and migration.44 However, it appears from animal models that there is a pool of progenitor cells available that can, under appropriate circumstances and in the absence of continued immune attack, regenerate myelinating oligodendrocytes.11,28 However, it would also appear that this pool of potential oligodendrocyte precursors is small and rapidly depleted.45 There appear to be two potential strategies for promoting myelin replacement in MS. While both are conceptually appealing, they have their potential drawbacks as well. One strategy might be to attempt to alter the cellular environment of the CNS so that it becomes more permissive, instead of inhibitory, to myelination by providing factors that promote the proliferation, migration, and maturation of oligodendrocytes. Oligodendrocyte precursors appear to originate from the O-2A precursor cell, so named because it gives rise to both oligodendrocytes and astrocytes. Several protein growth factors are involved in the maturational sequence of oligodendrocytes. Current evidence suggests that initial proliferation of oligodendrocyte precursors is driven by basic fibroblast growth factor (bFGF). Platelet-derived growth factor (PDGF) is also involved in the growth of oligodendrocyte precursors, as well as in migration. The intracellular signaling pathways activated by these growth factors include at least two members of the mitogen-activated protein kinase (MAPK) family as well as pp70 S6 kinase.11 Activation of cyclic AMP5 or the PDGF antagonist, trapidil,85 blocks growth factor-induced proliferation of oligodendrocyte precursors. Withdrawal of PDGF and FGF results in differentiation of oligodendrocyte precursors into mature oligodendrocytes.5 Insulin-like growth factors 1 and 2 appear to be survival factors for mature oligodendrocytes; transforming growth factor-beta (TGFβ) is also involved in the differentiation of oligodendrocytes, as is the neurotrophic factor neurotrophin-3. The complexity inherent in enhancing the gliogenic milieu of the CNS can be readily appreciated. The proliferation, migration, and differentiation of progenitor cells into mature, myelinating oligodendroglial cells require a precisely timed sequence of growth signals that, for the treatment of patients, must be delivered to multiple lesions disseminated in space and time, inherently differing

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Page 283in their states of demyelination and remyelination. Furthermore, the success of such a strategy depends on the availability of an endogenous pool of progenitor cells ready to be induced to divide, migrate, and mature into functional myelinating oligodendrocytes. Finally, the newly formed myelinating cells must be protected from further immune attack. An alternative strategy might be to supply the diseased MS brain with cells that would develop into mature oligodendrocytes, perhaps in conjunction with a source of the requisite growth factors. Many of the same caveats apply to such transplantation strategies as attempts to promote regeneration of endogenous myelinating cells. In addition, the potential for both immune rejection and malignant transformation of transplanted cells must be overcome. Specific Neuroprotective Agents Damaged neurons in the CNS attempt to repair themselves. These attempts are usually not successful and, as indicated previously, can lead to maladaptive effects. An important component of restoration of function, especially in a disease such as MS in which axons are damaged, must include the possibility of axonal repair. Several conditions interfere with attempts at axonal regrowth after lesions develop. These include the presence of a glial scar (depending on the site of the lesion), the lack of neurotrophic factors that support growth, or the presence of inhibitory molecules that impede axonal growth. One of the more promising approaches to encourage axonal growth is the administration of growth-supporting molecules, particularly specific growth factors. As noted above, axonal transection in areas of demyelination can lead to Wallerian degeneration and neuronal cell loss. Thus, agents that induce protective reactions in neurons or enhance axonal sprouting might preserve or promote recovery of neuronal function. Application of such strategies is not, however, without its challenges. Recent clinical trials of neurotrophic factors for the treatment of amyotrophic lateral sclerosis (ALS), which is a relatively simple, monophasic degenerative disorder of the motor system, have so far failed to produce positive results. Neurotrophic factors are large protein molecules. For therapeutic use, these complex molecules are synthesized in bacteria or cultured animal cells from which they can be purified and then administered by injection. To the best of our knowledge, systemically administered neurotrophic factors do not cross the blood-brain barrier. For the treatment of MS, it would seem that they must be administered directly into the CNS, either in soluble form via an implanted pump or using some novel cellular means of delivery such as transformed cells or direct gene therapy approaches. Small-molecule agonists and enhancers or inducers of neurotrophic activity are in development. Specificity is the final challenge of using neurotrophic factors to treat degenerative disorders, including MS. Many neurotrophic factors act only on certain cell types within the CNS. For example, the receptor for nerve growth factor

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Page 284 (NGF) appears localized to only basal forebrain cholinergic neurons and a few other cell types in the brain; receptors for the related trophic factor, brain derived neurotrophic factor (BDNF) are widespread throughout the cortex and subcortical structures. Neuronal damage in MS, however, affects axons belonging to multiple cell types, not all of which will necessarily respond to the same neurotrophic factors. In addition to having trophic actions on neurons, a number of neurotrophic factors, including neurotrophin-3 (NT-3), ciliary neurotrophic factor, and IGF-1, exert effects on glia. Many of the “neuroprotective” agents today are protein growth factors. Neurotrophins. The neurotrophins are a family of related 22-kDa proteins that are crucial for the survival and differentiation of neurons during development and in response to injury. They include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin 4/5 (NT-4/5).59 Originally discovered because of their ability to promote neuronal survival in vitro, the neurotrophins have been found to participate in many aspects of neuronal function, including plasticity, neurotransmitter synthesis and release and regulation of cytoskeletal proteins, receptor proteins, and so forth. The specificity of action of the neurotrophins is dictated by the distribution of their receptors. Neurotrophins bind to two populations of cellular receptors. The so-called low-affinity neurotrophin receptor (p75LNGFR) belongs to the TNF family and binds all members of the family with varying affinities. In some systems, occupancy of this receptor by a cognate ligand can prevent apoptotic cell death. The “high-affinity” receptors for the neurotrophins belong to the Trk family of tyrosine kinase receptors. The three members of this family TrkA, TrkB, and TrkC bind NGF, BDNF, NT4/5, and NT-3, respectively. NT-3 is somewhat “promiscuous” because it can bind to and signal through TrkA as well as TrkC. Neurotrophins can be produced by inflammatory cells. Both activated lymphocytes9 and glia49 possess neurotrophin receptors and can produce neurotrophins. Different cytokines stimulate different patterns of neurotrophin expression. Beta-interferon stimulates NGF production by astrocytes;14 activated lymphocytes and monocytes can produce BDNF.9,46 Thus, the neurotrophins appear to be expressed in the milieu of the MS lesion, perhaps as part of the reparative or restorative response. Neurotrophic factors can protect and rescue neurons in a large number of experimental models. Of particular relevance to MS is the demonstrated ability of BDNF and NT-3, in particular, to promote regeneration of long tracts in the spinal cord.117 Neurotrophins are also involved in the development and maintenance of glia, including oligodendroglia. NT-3 stimulates the proliferation of oligodendrocyte progenitors in vitro, and both NT-3 and NGF enhance the survival of differentiated oligodendrocytes in culture.20 NGF receptors are found on mature human oligodendrocytes.51 Intracranial injection of NT-3 appears to cause an increase in

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Page 285the proliferation of oligodendrocyte precursors and an inhibition of proteases involved in cell death signaling.48 The role of the neurotrophins in demyelinating diseases is presently unclear. Levels of NGF are increased in the CSF of MS patients,55 in the optic nerve of MS patients,73 and in the brains of animals with EAE.72 However, it is not known whether the increase in NGF is due to its release from inflammatory cells or whether it is part of a protective response of the CNS. There is no information available concerning the regulation of BDNF or NT-3 in animal or human demyelinating disease. Exogenous NGF can prevent autoimmune demyelination in marmosets.110 Whether this is due to inhibition of the immune attack or elicitation of protective responses in oligodendrocytes remains to be determined. BDNF has been studied in clinical trials in ALS, although the initial results suggested that the doses studied might have been too low.7 Subsequent studies are examining the safety and efficacy of BDNF administered either at systemic doses higher than those studied in the original trial or intrathecally. These studies are in progress at the time of this writing. Nerve growth factor and NT-3 have both been studied in peripheral neuropathy patients, but not in CNS disorders. Neuropoietic Cytokines. Neuropoietic cytokines are the family of neural growth factors that act on both the nervous and the hematopoietic or immune systems, and which include ciliary neurotrophic factor (CNTF). CNTF is further a member of the interleukin-6 (IL-6) family of cytokines. It was originally isolated from ocular tissues as a protein factor that supports the survival of ciliary ganglion neurons in cell cultures and from the cytoplasm of myelinating Schwann cells of peripheral nerves. It has neuroprotective properties in a number of in vitro and in vivo systems, including models of motor neuron disease and spinal cord injury. CNTF appears to protect oligodendrocytes from TNF-induced cell death in vitro.21,65 CNTF has been studied in clinical trials of patients with ALS by both subcutaneous and intrathecal routes of administration.2,83 When administered subcutaneously, CNTF did not affect the course of disease in ALS patients, and the stability of the pharmaceutical formulation limited its use via the intrathecal route. Other Growth Factors. Glial cell line-derived neurotrophic factor (GDNF) is a member of the TGF-β family of growth factors. GDNF was originally discovered based on its ability to support the survival of embryonic dopamine neurons in tissue culture. It was subsequently discovered to have effects on several classes of CNS neurons including corticospinal tract cells.43 GDNF has been studied in clinical trials using intracerebroventricular administration in patients with ALS and Parkinson's disease. These trials were stopped due to the severe side effects of the drug. Insulin-like growth factor 1 (IGF-1) is a 7.65-kDa polypeptide that has multiple endocrine, metabolic, and neurotrophic actions.42 It is structurally and func-

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Page 286tionally related to insulin, and its effects are mediated through a tyrosine kinase receptor of the insulin receptor family. The activity and distribution of IGF-1 are tightly modulated by a group of IGF-specific binding proteins. IGF-1 participates in the development of neurons and glia, and its expression in the developing brain correlates spatially and temporally with the onset of myelination.56 Myelin content is increased in the brains of mice that overexpress the IGF-1 gene17 and decreased in IGF-1 knockout animals. The IGF-1 gene is induced in reactive astrocytes by experimental demyelination47 and in human MS lesions.31 In vitro, IGF-1 can protect oligodendrocytes from TNF-induced injury;119 cellular survival under appropriate conditions can be affected by the balance between IGF and TNF signaling due to cross-talk between postreceptor signal transduction cascades.108 IGF-1 also modulates the activity of immune-competent cells. Several recent studies have suggested that systemically administered IGF-1 can ameliorate EAE in animals.60 IGF-1 has been studied in clinical trials in ALS with inconclusive results. “Gliotrophic” Factors. Oligodendroglial precursor cells respond to several growth factors in the course of their development. Signaling through some of these same pathways appears to be important for remyelination and proliferation of oligodendrocyte progenitor cells in the injured adult CNS as well. IGF-1 has already been mentioned, but it is only one of several growth factors that are important in oligodendroglial function. Some of these molecules can ameliorate the course of EAE. Fibroblast growth factor-2 (FGF-2) and thyroid hormone influence early pluripotential glial precursors to develop into oligodendrocytes. Platelet-derived growth factor controls the migration and proliferation of later-stage oligo precursors (see 1999 review by Rogister et al.87). Glial growth factor 2 (GGF-2; neuregulin), a member of the epidermal growth factor family, promotes survival and proliferation of pre-oligodendrocytes, but prevents differentiation to fully mature cells.16 GGF-2, however, has been reported to delay onset, decrease severity, and reduce relapse rate in a murine EAE model.67 Yet another neurotrophic factor, ciliary neurotrophic factor (CNTF), has been shown to protect oligodendrocytes from TNF-mediated cell death.65 Augmentation of Local Mechanisms Neurotrophic factors might be produced in the MS lesion itself. For example, NGF is increased in inflammatory foci and in the CSF of MS patients. Interleukin-1 can stimulate astrocytes to synthesize NGF, which is probably the mechanism through which NGF is increased in inflammatory foci. Therapeutic enhancement of local neurotrophic factor production is a pathway worth exploring.

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Page 287 Small Molecules There are many small molecules that can protect neurons. These include glutamate antagonists, neuroimmunophilins, and nitric oxide and are discussed in turn below. Riluzole is a putative neuroprotective agent that can modestly prolong survival in ALS74 patients. It is believed to work by blocking neuronal glutamate release and is currently being studied in other neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease. Activated macrophages in MS lesions appear to release glutamic acid, as well as other potentially neurotoxic molecules. Neurons possess two types of glutamate receptors, both of which might participate in the neurotoxic effects of glutamate: NMDA and AMPA/kainate receptors. Oligodendrocytes also carry AMPA/kainate receptors. Recent studies have suggested that, like neurons, oligodendroglia might be susceptible to AMPA/kainate receptor-mediated glutamate excitotoxicity.69 Glutamate antagonists have been found to ameliorate myelin damage in an EAE model.32,113 AMPA antagonists are currently under study in stroke and neurodegenerative disease trials. Exploration of AMPA antagonism in MS is warranted as both a neuroprotective and a glioprotective strategy. SR7657A is a small molecule that has been found to enhance and/or mimic the effects of neurotrophins in tissue culture. It is currently being studied in ALS. Thus far, studies of SR7657 on the course of ALS have failed to demonstrate a statistically significant effect of the drug, as measured by the trials' chosen end points. Neuroimmunophilins are cyclosporin-related molecules that inhibit the signaling pathways that lead to cell death. They have been reported to protect brain dopamine neurons from injury and are currently being tested in early-stage clinical trials in Parkinson's disease. Nitric oxide is a small, highly reactive molecule that is normally a gas at room temperature. It is synthesized in biological organisms where it exists as a highly lipid-soluble, dissolved nonelectrolyte solute. NO diffuses rapidly in tissues and enters into redux reactions via its unpaired electron. It is less reactive than other free radical species. Under appropriate conditions, NO is synthesized by one of a family of nitric oxide synthase (NOS) enzymes. It reacts with superoxide anion to produce peroxynitrite (ONOO−), a highly reactive substance that can interact with and modify proteins, lipids, and nucleic acids. NO is produced as a neurotransmitter in certain neurons and is also produced by endothelial cells and by active inflammatory cells.22 The inducible form of nitric oxide synthase (iNOS) has been localized in active MS lesions in human brain specimens.12 Selective inhibitors of both the neuronal (nNOS) and inducible (non-neuronal, iNOS) enzymes are becoming available18 and might be another class of neuroprotective and glioprotective agents that merit testing for their therapeutic value in MS.

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Page 314trials, even when randomized, can give misleading results. Even when randomized trials are performed, enrolled patients often represent only a small proportion of the target population and may not be representative of the larger group. With the participation of many centers in a prospective, observational database, large numbers of subjects representative of the general population can accrue rapidly. This increases the power to detect meaningful changes in outcome and increases the precision with which outcomes can be measured. It is important to emphasize that studies of observational data from multiple centers do not replace the need for carefully conducted, single-center, Phase I and II studies and single- or multicenter randomized studies. Rather, they offer a complementary approach for addressing issues and can help facilitate trials. The database serves as an efficient source of information for evaluating new treatments, especially in the preliminary stages of investigation. It also provides information that is unlikely to be extensively pursued in industry-funded clinical trials—for example, long-term effects, continuation of therapy, and different responses to different therapies. In addition, a large, longitudinal database such as the IBMTR-ABMTR is uniquely suited to late and infrequent effects of transplantation—or any other long-term consequence such as accumulated disability in the case of MS. Since the mid-1990s, HSC transplantation has been used to treat a variety of autoimmune diseases in about 300 patients. Some, but not all, have shown long-lasting improvement, and many issues require further clarification through coordinated clinical trials. The European Bone Marrow Transplant (EBMT) group is working with IBMTR-ABMTR to develop consensus and standardization for data collection related to HSC transplantation in patients with autoimmune disease, as well as guidelines for trials and patient selection. There are 35 full-time staff dedicated to the registry, including physicians, statisticians, database managers, and a development office for fund raising. The activities of the IBMTR and ABMTR are supervised by more than a dozen volunteer committees that design and conduct studies, develop general policies for use of IBMTR and ABMTR data, review study proposals, and plan and conduct scientific workshops. The success of the registry programs is due, in large part, to the voluntary efforts of the hundreds of physicians, basic scientists, and clinical research associates who contribute their time and expertise. The annual budget for the IBMTR is about $3 million, with about 60 percent of the funding coming from the National Institutes of Health (Melody Nugent, personal communication). The remaining support comes from corporations, foundation grants, and individual donors. The major expense of the registry is for reimbursement of fully participating centers, who are asked to submit their data in a 75-page form. Institutions can also participate on a limited basis, in which case they submit reports with only 20 items and are not reimbursed for their services. The registry is supported by the Medical College of Wisconsin, the Department of Defense, and the following institutes within the National Institutes

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Page 315of Health (NIH): National Cancer Institute; National Institute of Allergy and Infectious Disease; and National Heart, Lung and Blood Institute. Comparable data registries for multiple sclerosis would be invaluable. Each of the challenges presented by transplantation is mirrored in those presented by MS. Most importantly, such registries provide a larger data set than would be possible through individual efforts. Although such registries are likely to receive generous federal and industry support, they should be led through collaborative public and nonprofit efforts. An independent, investigator-driven database will likely have more scientific credibility than for-profit ventures and thus ultimately be of greater value to investigators as well as pharmaceutical firms. The IBMTR-ABMTR includes data on MS patients, but only in the context of transplantation. The most efficient approach for MS research might be to develop a database that would permit comparison with the IBMTR-ABMTR database. Human Tissue in MS Research The scientific value of human tissue is immeasurable. A small amount of diseased human tissue can reveal clues to a disease that no other research strategy can. For MS research, brain tissue is crucial, but this can be obtained only after death or by biopsy. However, brain biopsy for research purposes is generally not possible because of the risk of brain injury to the patient, which means that researchers must rely on postmortem tissue. In terms of understanding disease mechanisms and developing therapeutic interventions, the most informative tissue would be that of MS patients in the earlier stages of diseases, but these patients are generally young and less likely to die than patients in the later stages of MS. Another complicating factor is that unless brain tissue is processed quickly and according to standard protocols, it degrades to the point where is useful only for relatively crude research techniques, and not for the newer genetic and molecular techniques. Access to tissues from a wide array of MS patients either with different disease phenotypes or in different phases of the disease not only permits important research on the pathogenesis of the MS disease process, but enables research on the specific causes of neurologic disability, as well as disease heterogeneity. Tissue collection from patients is complex, and cooperative efforts are necessary to achieve sufficient numbers. Some tissues are readily available, such as peripheral blood samples and CSF. Others, such as brain tissue, are not. Collections of serum and lymphocytes have been built into many natural history and clinical trial studies. Access to such samples has, for the most part, involved collaborations with those who collected the samples. At issue is whether such samples will be stored in optimal condition, which is particularly important with regard to serial samples needed to study the natural cause of disease.

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Page 316 Lymphocyte samples are valuable with regard to both RNA- and DNA-based investigations. RNA would be the basis for evaluating single molecules as well as for use in the emerging DNA microarray technology. DNA is used for the molecular genetic analyses aimed at identifying disease susceptibility genes or genes that modulate disease course. The challenges of collecting, storing, and sharing such resources are dealt with in other sections. CSF fluid is becoming more difficult to obtain because sampling for diagnostic purposes is done less routinely than in the past. Although private CSF banks continue to exist, most tend to have samples suitable for analysis of the fluid but not for any of the cell constituents that were present (RNA is needed to measure gene expression, but it is highly degradable under normal tissue storage conditions). Brain and Tissue Banks Many brain banks, wherein patients arrange to donate their brains after death, have been established for the advancement of research in a variety of neurological disorders, most commonly Alzheimer's disease. These brain banks have been instrumental in identifying the mechanisms of Alzheimer's disease and should prove equally useful in MS research. However, MS is less prevalent than Alzheimer's disease, and there are fewer available samples. Thus, it is important to be sure that any available tissue is collected using protocols that will optimize its scientific value—for example, by establishing standards for collection, quality control, and collaborations among multiple centers. Finally, brain banks require concerted outreach efforts since this need is not something of which the public is generally aware. CNS tissue from cases of MS has been collected for many years at many institutions, forming the basis for the classical pathologic descriptions of the disease. As expected, the majority of tissues were collected from long-standing cases. Most of the early disease stage samples represent the most aggressive form of the disease. Samples were not usually preserved in a manner that is ideal for optimal immunohistochemical or molecular analyses. A number of brain banks have been established over the years. Limitations of these collections include the paucity of clinical information available on the cases and the lack of recent modern neuroimaging investigation. The NIH currently funds 14 brain banks, several of which also receive funding from other sources. Ten of these banks are for research into Alzheimer's disease, and none of them collect tissue from MS patients. The MS Society has funded two brain banks for many years. One is at the Veteran's Administration in California and includes tissue collected from patients with a variety of neurological diseases in addition to MS. The other is in Colorado and collects only tissue from MS patients. According to user surveys conducted by the MS Society, the needs of researchers have been adequately met by these brain banks. There are

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Page 317also MS brain banks in Britain and in the Netherlands. The latter provides services unmatched by any other MS brain bank (Box 6.3). The amount of brain tissue at the British brain bank has been too limited to supply researchers outside BOX 6.3 Netherlands Brain Bank The Netherlands Brain Bank was organized in 1985 and, in 1990, established its program related to MS, whose main purpose is to obtain rapid autopsies from which tissues can be used for studies in neuropathology, immunocytochemistry, molecular biology, and tissue culture. The tissues are properly prepared for special studies, and the program has the flexibility to initiate new procedures. Sufficient amounts of all tissues are retained for potential follow-up for future studies. Thus far, 110 MS autopsies have been performed, averaging 10 to 12 cases per year. The program also emphases obtaining “control” autopsies, of which about 30 or more are performed annually. Only about 10 percent of the rapid autopsy cases performed are for MS; the control cases (20 to 30 percent) are also part of the program. The brain bank also obtains cases of various other neurological diseases, with an emphasis on Alzheimer's disease (30-40 cases per year). Overall, the brain bank team performs 100 to 120 rapid autopsies per year. Of note, the protocols involved in an MS autopsy include MRI pathology studies and lesion dissection, which result in such cases taking three to four times longer (six to seven hours) than many others. The tissues must be analyzed as completely as possible, ideally including assessment of the extent of tissue injury, activity of the disease, and extent of remyelination. Indeed, a key strength of this program is the ability to perform MRI scans in the middle of the night. The MRI-pathology correlation effort of the brain bank is internationally recognized. This effort includes postmortem in situ imaging, as well as imaging of tissue sections. The approach of using MRI-defined lesions to direct the site of neuropathology examination, as well as more traditional MRI correlation with pathologically obvious lesions, is considered very promising. Because it is part of the larger brain bank, the MS brain bank can share the highly expert staff (secretaries, pathologists, technicians, and undertaker) who are available full-time. Without this type of infrastructure, the rapid response to MS cases could not take place. There is a well-established program in which patients agree to tissue donation. Donations are organized through direct efforts of the brain bank with the public. The entire staff is attuned to the ethical issues and specific restrictions on tissue access opportunities that exist in the Netherlands. There is increasing demand on the bank for tissue, and an impressive number of research papers have been published using its materials. A 1999 review of the program indicated that it should be able to deal with any concern within the Netherlands regarding access to this national resource. Established users of the bank pay an annual subscription fee of 3000 df ($1,100 U.S.). Commercial companies are charged at higher rates. There is also a “pilot” program for which no charges are made. The brain bank is funded approximately equally by the Dutch MS Society, the hospital in which it operates, and research grants.

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Page 318 Britain, and tissue distribution from the Netherlands brain bank has been largely restricted to European researchers. Finally, some researchers maintain their own brain banks and do not publicly distribute the tissue. Private collections are necessary for researchers who need to tailor tissue collection procedures for specific research techniques. The issue of access to cases of MS early in the disease course remains an unresolved challenge. Surgical samples are available mainly from cases that represent diagnostic difficulties and cannot be expected to be representative of all early MS cases. These patients can be followed and their subsequent disease course established. They provide an excellent opportunity to correlate neuroimaging data with tissue analyses. The hope is to establish imaging criteria that will correlate with the suspected different pathologic forms of MS. Serial samples are not likely to be available from these cases. Additional surgical samples may become available if other invasive therapies such as deep brain stimulators come into use to treat some of the disabling symptoms of MS such as tremor. Combined with the increased demand, the limitations in obtaining MS tissues for research studies suggest a need for international cooperative efforts. Such efforts would include ensuring that all those involved in tissue collection aim to meet the ideals described above with regard to tissue handling. Collected tissue should be preserved to allow as many types of analyses as possible. Specifically, tissue collection and storage protocols that allow for histologic, immunocytochemical, and molecular analyses should be established and consistently followed. Tissues that are to be provided to investigators for biochemical and molecular analyses of disease activity must be carefully evaluated pathologically. Standard criteria for rating disease activity would improve comparisons between different studies. It is also important to have facilities that can respond rapidly when cases of MS become available for postmortem analyses, including the ability to perform immediate pre-autopsy MR scanning and scanning of tissues immediately after collection. Education of MS patients about the value of such programs is also important. As discussed under communication in Chapter 4, it is important that patients and their families participate in the development of informational materials. The protocols of the Amsterdam brain bank offer an instructive model for brain banks in other countries (Box 6.3). REFERENCES 1. Akizuki M, Reeves JP, Steinberg AD. 1978. Expression of autoimmunity by NZB/NZW marrow. Clin Immunol Immunopathol.; 10: 247-50. 2. ALS CNTF Study Group. 1996. The Amyotrophic Lateral Sclerosis Functional Rating Scale. Assessment of activities of daily living in patients with amyotrophic lateral sclerosis. The ALS CNTF treatment study (ACTS) phase I-II Study Group. Arch Neurol.; 53: 141-1. 3. Antel JP, Becher B, Owens T. 1996. Immunotherapy for multiple sclerosis: from theory to practice. Nat Med.; 2: 1074-5.

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