Multiple Sclerosis Current Status and Strategies for the Future (2001) / Chapter Skim
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6 Future Strategies for Therapies
6 Future Strategies for Therapies
Pages 277-324
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From page 277... ...
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.
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From page 278... ...
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)
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From page 279... ...
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.
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From page 280... ...
Immunocleviation Approach potential involves inducing immunodeviation of myelin-specific T cells, that is, shifting the balance of production from Thl to Th2 cells. This is a crowded field in MS research, as in other putative autoimmune diseases.
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From page 281... ...
Such strategies might include administration of gliotrophic factors or transplantation of glial precursors or stem cells that repopulate demyelinated regions of the CNS.~2 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.
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From page 282... ...
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 mitogenactivated protein kinase (MAPK)
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From page 283... ...
Many neurotrophic factors act only on certain cell types within the CNS. For example, the receptor for nerve growth factor
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From page 284... ...
Many of the "neuroprotective" agents today are protein growth factors. Neurotrophins.
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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)
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From page 286... ...
, a member of the epidermal growth factor family, promotes survival and proliferation of pre-oligodendrocytes, but prevents differentiation to fully mature cells.~6 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.
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From page 287... ...
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.
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From page 288... ...
In in vitro experimental models, drugs that block the Na+~Ca2+ exchanger or sodium channels can protect axons so that they do not degenerate following injury.25 99 i00 Neurotransmitters and neuromodulators such as y-aminobutyric acid (GABA) and adenosine appear to have a modulatory effect on the axonal injury cascade within white matter, and indeed, GABA and adenosine have a neuroprotective effect in white matter where they can preserve axonal function after various insults.26 Calcium channels also appear to play a role in admitting injurious calcium into axons following some injuries.29 Blocking calcium channels, as well as sodium channels, thus should be considered in the search for neuroprotective strategies that will preserve axons in MS.
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From page 289... ...
Many MS patients have been treated with intrathecal baclofen for spasticity using an implanted pump. Recent clinical trials in ALS with BDNF82 and CNTF83 have demonstrated the feasibility of this method for delivering protein therapeutics to the CNS.
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From page 290... ...
CNS Repair and Restoration Strategic Questions About Remissions The converse of the concept of relapse prevention, which has driven the most recent round of clinical trials in MS, is the concept of active induction of remission. Remissions, in which there is restoration of necrologic function, such as vision or the ability to walk, that had previously been lost, commonly occur in multiple sclerosis.
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From page 291... ...
Molecular neuroscience can teach us more about the molecular mechanisms that are responsible for synthesis and deployment of sodium channels in myelinated and demyelinated axons and about ways to manipulate channel distribution along the demyelinated axon therapeutically. A third scenario is that other mechanisms of plasticity, such as synaptic sprouting or recruitment of previously uninvolved parts of the brain and spinal cord, can compensate for demyelination and even axonal loss early in the disease course, but that these processes become overwhelmed as the burden of disease accumulates, so that they can no longer contribute to recovery.
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From page 292... ...
Strategies to control rejection, induce tolerance, and enhance xenograft survival have to be developed, and the mechanisms underlying xenoreactivity must be better defined. Stem Cells A mature animal originates from a single cell, which initially has the potential to produce a diverse array of tissues, organs, and cells.
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From page 293... ...
Although these cells do not seem to engage independently in neural repair, it might be possible either to isolate and harvest a pluripotential population of stem cells or to induce endogenous self-repair by administering the appropriate growth factors or other substances that will induce these cells to differentiate and repopulate lesioned sites. Until recently, the concept of a neural stem cell was not considered because the CNS has been regarded as a structure incapable of regeneration.
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From page 294... ...
Circulating marrow-derived cells can reenter the brain and migrate into the ventricular zone, as well as differentiate into microglial cells and astrocytes. FGF-2 denotes fibroblast growth factor 2; EGF, epithelial growth factor.
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From page 295... ...
Stem cells can also be transfected with viral vectors that allow the delivery of substances capable of inducing neural repair. Various growth factors have been successfully induced in neural stem
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From page 296... ...
, and encouraged axonal growth from host axons. Many other studies report positive findings after delivery of growth factors into lesioned spinal cord, including functional improvements in gaited 63 84 Bone Marrow Transplantation.
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In allogeneic transplants, previously extracted marrow from a different donor provides the stem cells for transplantation to a genetically different recipient. Both types of bone marrow transplantation have an impact upon autoimmune diseases.
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From page 298... ...
. The National Multiple Sclerosis Society has been highly effective in proactively addressing many of these issues through its Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis and its Clinical Outcomes Assessment Task Force and Task Force on Use of MRI in MS Clinical Trials.
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From page 299... ...
MS is a difficult disease to study, and the potential market for profit-dependent firms is small relative to the investment needed to produce an approved drug. Specific challenges to the design of MS clinical trials include the general challenges presented by therapies that alter immune responses, therapies for which there is so much demand that they are applied even before solid clinical data are available; situations in which placebo controls are not appropriate, despite the
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From page 300... ...
An example is the Airlie House guideline for clinical trials in amyotrophic lateral sclerosis, which were formulated by a working group of the World Federation of Neurology.32 The authors of this document included academic physicians, pharmaceutical company representatives, and representatives of the Food and Drug Administration (FDA)
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From page 301... ...
The proper choice of control groups is an issue that affects any clinical trial but becomes especially difficult for MS clinical trials as patients gain access to more effective therapies. Asking individuals to forgo effective treatment is an unacceptable option.
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From page 302... ...
In the case of transplantation-based treatments, such as stem cell and bone marrow therapies, blinding would require sham surgeries, which can be unethical or impractical. When a study cannot be blind, it may be possible to reduce bias by having the outcomes assessed by individuals who are blinded to the treatment.
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From page 303... ...
Several principles are critical in developing such targeted therapies, including the use of validated, standardized outcome measures in the trial, well-defined criteria for participating in a clinical trial and for defining patient subsets, storage of samples from patients for use in validating future tests as methodologies evolve, and finally, giving early consideration to developing a test that will be broadly available clinically should the need arise. Response to Withdrawal of Therapy For any therapy that modulates the immune response, time-course studies are needed.
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From page 304... ...
Assessment Instruments The development and validation of efficient, accurate, sensitive and reproducible assessment instruments is critical to the success of clinical trials. As noted in Chapter 4, the MS Society has contributed to this area by promoting the development of the Multiple Sclerosis Functional Composite Measure (MSFC)
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From page 305... ...
, has been developed and validated under the aegis of the Consortium of Multiple Sclerosis Centers and the National MS Society.27 Neuroim aging The rapid advance in the development and sophistication of magnetic resonance imaging techniques is detailed elsewhere in this volume. Whereas some measures, for example gadolinium enhancement, are most sensitive to acute blood-brain barrier breakdown and inflammation, other measures such as assessments of brain volume or atrophy give a better picture of accumulated tissue loss.
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From page 306... ...
It seems unlikely that dramatically improved clinical scales can be developed given the rate of disease progression. Finally, even when the same clinical outcome measures have been used, it is not always statistically valid to compare different clinical trials.
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From page 307... ...
In 1994, an international group of experts convened by the MS Society concluded that MRI could serve as a primary outcome measure in Phase II or exploratory clinical trials but that it should be used only as a secondary outcome measure in Phase III or pivotal trials. The recent approval and widespread use of several partially effective therapies for MS have changed the options for testing new therapies and, as a result, interest in using MRI as an outcome measure has intensified.
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From page 308... ...
The condition placed on the use of an unvalidated surrogate is that the surrogate outcome must be considered reasonably likely to predict future clinical outcome or disease activity. As discussed below, studies to date that have examined the relationship between MRI measures of disease and clinical disease either in cross section or as future disease have been, with one notable exception, disappointing.
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From page 309... ...
However, there is evidence to support the concept that various MRI changes reflect changes in the underlying pathology of the disease, and consequently, it has been suggested that under some conditions, MRI changes can be appropriately used as a primary outcome measure in pivotal trials in MS. In other words, the changes in MRI measures can appropriately serve as an unvalidated surrogate for changes in pathology.
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From page 310... ...
Various MRI measures are listed in Table 6.1. TABLE 6.1 MRI Outcomes for Clinical Trials of New Agents Aimed at Preventing Relapses or Slowing Progression: Recommendations of the November 1999 Workshop Convened by NINDS and the MS Society.
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From page 311... ...
Overall, the use of MRI as a surrogate outcome measure is an attractive possibility at a time when clinical trials using conventional clinical outcomes in placebo-controlled studies that require large numbers of patients and a long duration are becoming increasingly problematic. However, the use of MRI as a currently unvalidated surrogate must be approached with caution and with careful thought to the potential errors that could result as well as the possible benefits.
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From page 312... ...
There is general agreement that doubleblind placebo-controlled clinical trials for relapsing-remitting multiple sclerosis, of a size and duration such as have been necessary in the past to demonstrate effectiveness, are no longer ethically justified. Such trials can be justified in certain small clinical subgroups of patients, but their results cannot be assumed to apply to MS patients as a whole.
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From page 313... ...
The information gathered by the IBMTR and ABMTR is used to identify trends in transplant use and outcome, to guide physicians and patients in making treatment choices, and to conduct scientific studies of issues pertinent to improving transplant outcomes. Researchers planning clinical trials use the database to aid study design; they are an invaluable resource for estimating effect sizes, targeting appropriate study populations, designing efficient protocols, and determining accrual feasibility.
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From page 314... ...
Some, but not all, have shown longlasting improvement, and many issues require further clarification through coordinated clinical trials. The European Bone Marrow Transplant (EB MT)
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From page 315... ...
Comparable data registries for multiple sclerosis would be invaluable. Each of the challenges presented by transplantation is mirrored in those presented by MS.
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From page 316... ...
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.
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From page 317... ...
The amount of brain tissue at the British brain bank has been too limited to supply researchers outside
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From page 318... ...
1996. Immunotherapy for multiple sclerosis: from theory to practice.
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From page 319... ...
1990. Clearance of severe psoriasis after allogenic bone marrow transplantation.
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1999. Insulin-like growth factors and binding proteins in multiple sclerosis plaques.
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1989. Reciprocal allogeneic bone marrow transplantation between NOD mice and diabetes-nonsusceptible mice associated with transfer and prevention of autoimmune diabetes.
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1999. Altered nerve growth factor level in the optic nerve of patients affected by multiple sclerosis.
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From page 323... ...
diabetes mellitus and hypothyroidism after allogeneic bone marrow transplantation in a patient with lymphoblastic leukaemia. Diabetologia.;36:541-546.
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1997. Growth factors and myelin regeneration in multiple sclerosis.
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