Future Research Directions in Multiple
`Sclerosis Therapies
`
`Benjamin M. Greenberg, M.D., M.H.S.,' and Peter A. Calabresi, M.D."
`
`ABSTRACT
`
`The success of presently available injectable immunomodulatory therapies in
`treating multiple sclerasis has led to heightened interest in finding even more efficacious
`and better tolerated therapics. Several oral agents have shown efficacy in phase-]] clinical
`trials and are nowentering phase-T]] pivetal
`trials. In addition, monoclonal antibodies
`targeting surtace receptors on various cells of the peripheral immunesystem have also shown
`efficacy in carly stucles and will soon be entering phase HL. All of these approaches target
`immune molecules that are not specific for multiple sclerosis (M5) and carry inherent risk of
`infection and systemic side effects. Novel immunotherapies m preclinical or phases I to Ha
`testing arc attempting to more selectively target pathogenic effectorcells and thereby block
`abnormal immunecell activation without compromising normal healthy immuneresponses.
`The induction of tolerance to self-proteins continues to be a goal ofMS immunotherapy, bur
`as yet has not been accomplished outside ofthe laboratory. There is increasing awareness of
`the need to understand and modulate nonclassical immunetargets as well as central nervous
`system degenerative processes. The roles ofvitamins, antimicrobials, and hormones continue
`to be studied. The mechanisms of ncurodegeneration in MS are likely multifactorial and
`include direct damage byTcells and humoral immunityas well as oxidative stress, elutamate-
`mediated excitotoxiciry, and neuronal andoligodendrocyte apoptosis. Neuroprotective drugs
`that were once onlyconsidered for classical degenerative diseases, such as amyotrophic lateral
`sclerosis and Parkinson's disease, are now being considered in MS.
`
`KEYWORDS: Monoclonal antibodies, immuncsuppression, neuroprotection, clinical
`trials, multiple sclerosis
`
`Despite the availability of six immunomodulat-
`ing drugs, there remains a dire need for more effective,
`safer, and more tolerable therapeutic agents for multiple
`sclerosis (MS). MS is a heterogeneous disease with a
`variety of different clinical and pathological subtypes and
`stages, and itis likely that we will need different combi-
`nations of therapeutic strategies to adequately treat all
`patients with MS."* Inthis article, experimental immu-
`notherapeutic approaches, for which there arc already
`positive phase-H clinical trial data, are considered first,
`
`immunotherapeutic strategies that
`followed by novel
`affer hape for greater selectiviry or safery. Finally, we
`consider strategies for neuroprotection and neurorepair.
`
`IMMUAIOTHERAPIES IN DEVELOPMENT
`
`Currently Available Therapies
`We are fortunate to have several treatment options for
`relapsing-remitting MS (RRM&). However,thefirst-line
`
`"Department of Neurology, Johns Hopkins School of Medicine,
`Baltimore, Maryland.
`requests: Peter A.
`Address
`for correspondence and reprint
`Calabresi, M.D,, Associate Professor, Depariment of Neurology,
`Jobas Hopkins School of Medicine, G0 North Woife Street,
`Pathology 627, Baltimore, MD 21287 (e-mail: calabresi@jhmtedu).
`
`Multiple Sclerosis and the Spectrum of CNS [aflammatery Demye-
`linating Diseases; Guest Editor, Claudia F. Lucchinerti, M.D.
`Semin Neurol 2008;28:121+128. Copyright
`¢
`2008 by Thieme
`Medical Publishers,
`[ne., 333 Seventh Avenue, New York, NY
`10001, USA, Tel: +1{212) 584-4662,
`DOT 10.1055/s-2007- 1019133, ISSN 0271-8235,
`
`Page 1 of 8
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`Biogen Exhibit 2224
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`IPR 2018-01403
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`122
`SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 1 2008aRtRARALAreeerAAtETAterent
`
`
`
`immunomedulating drugs (EMLDs) approved for MS
`(glatiramer acetate and interferon B) are an average
`only one-third effective in reducing relapses and have
`only modest benefits on progression of disability, ~* The
`shortcomings of these therapies likely relate to either
`potency of immunosuppression or specificity for
`the
`pathological processes involved in MS pathogenesix. To
`this point, mitoxantrone and other potent immunemo-
`dulating drugs have shown increased efficacy compared
`with TIMDs ia reducing or abrogating relapses, but carry
`risk of significant toxicities and still have no benefits in
`purelyprogressive types or stages of MIS. Natalizamab, an
`anti-w-4 integrin monoclonal antibody, was designed to
`inhibir immune cell migration by interfering with very
`late activation (VLA}4 interactions with endothelium
`and matrix proteins. This drug suppresses relapses by
`67%, and after 2 years of treatment 28%6 ofpatients were
`free ofanytype ofclinical or magnetic resonance imaging
`(MRE) disease activity compared with only 6% in the
`placebo group.” Unfortunately, despite hopes thar it
`might selectively target pathogenic cells, three cases of
`progressive multifocal leukeencephalopathy (PML, have
`occurred in patients on natalizumab in combination with
`other immunosuppressive medications,”* At this time, it
`is unclear whether this rare side effece
`out of 3000
`patients exposed in trials) is related to impaired immune
`surveillance of the central nervous system (CNS) or
`perhaps premature release of JC virus-infeeted B cells
`from the bone marrow duc to impaired interactions of
`these cells with the marrow sinusoidal vascular cell
`adhesion molecule
`(VCAM)-1 (a VLA-4 ligand).”
`Because VLA-4 is actually expressed on all activated T
`cells, B cells, and, to some extent, on monocytes, it may
`be too broad an immunecell target. Indeed, other CNS
`and systemic infections remain a concern in patients on
`this therapy. Thus, there remains a need for mare specific
`therapies that could inhibit pathogenic MS-related in-
`flammation without compromising the immunesystem’s
`ability to mount successful antimicrobial responses.
`
`Drugs in Clinical Trials
`The National Multiple Sclerosis Sociery (NMSS) Website
`(www.NMSS.org) lists more than 100 different clinical
`trials of therapeutic approaches being tested for MS. The
`vast majority ofthese are smal exploratorytrials or combi-
`nations of presently marketed dregs with experimental
`agents added on.In this article, we emphasize drugs in
`advancedclinical trials and newagents that have promising
`results in phase-IE studies. These are most simply
`dividedinto oral therapies and monoclonal antibodies.
`
`Oral Immunomedulatory Agents
`The immunemoedulator FTY720 (fingolimod)
`sphingosine-1P (S-1P) receptor agonist that
`is given
`
`orally ence per day. The S-1P1 receptor, which is the
`major target offingolimod, is found predominantly on
`naive and central memory lymphocytes; agonism ofthe
`receptor mediates down modulation, resulting in inhib-
`ition of lymphocyte egress from lymph nodes and thy-
`mus, but without any compromise of lymphocyte
`functionn (activation, proliferation, and cytokine produc-
`tion)! In a recens phase-I] clinical
`trial, FTY720,
`given either at 5 mg or 1.25 mg, resulted in an 50%
`reduction in clinical relapse rate and 80% reduction in
`MRI activity at 6 months"? A 24-manth open label
`extension has shownsustained efficacy and a predictable
`side effect profile consisting of jow-level
`increase in
`transaminases, first-dese bradycardia, and rare reports
`of pulmonaryfunction changes and macular edema. Two
`large phase-I1I trials are underway comparing fingoli-
`mod at 1.25 me and at a lower dose of 0.5 mg to
`placebo.
`BG12 is a second generation fumaric acid ester.
`The active ingredient, dimethylfumarare (DMF), has
`been shown to have both antiinflammatory and neuro-
`protective effects,’* DMF decreases proinflammatory
`eytokines and has proven efficacy in psoriasis.’" In
`addition, preliminary data have implicated DMF in the
`regulation of a pathwayfor detoxification that is central
`to protection ofcells from metabolic and inflammatory
`stress. A phasc-H studydesigned to evaluate the efficacy
`and safety of BG12 in patients with RRMS met
`its
`primaryendpoint. Treanment with BO12 at the highest
`dose, 240 mg three times a day, led to a 64% reduction in
`the total number of gadolinium (Gd)-enhancing brain
`lesions measured by MRI after 6 months of treatment
`versus placebo.
`In chis small study,
`the reduction in
`relapse rate was 32% and not significantly differen:
`compared with placebo, but 12-moarth open-label ex-
`tension suggests continued decline in the relapse rate.
`BG12 was generally safe and well tolerated. Common
`adverse events associated with BG12 included headache,
`gastrointestinal (GI) symptoms, flushing, and clevated
`transaminases.
`Laquinimed (ABR-215062) is related to lino-
`mide, an oral drug that showed efficacy in MS but was
`abandoned due to cardiotoxicity (scrositis, myocardial
`infarction). ' Laquinimod has high oral bioav:ailability
`without the toxicity, and has demonstrated inhibitory
`activity on autoimmune and inflammatorydiscases in
`animal models.'? A recent phase-Il study showed that
`laquinimod reduced the numberof active MRI lesions by
`4406, but there was ne significant reductionin relapses or
`disability.'* Higherdoses are being tested presently.
`Teriflunomide is a dihydro-orotate dehydrogen-
`ase inhibitor that has immunomedulatory effects,
`in-
`cluding the ability to suppress experimental allergic
`encephalomyelitis (EAE)."” A phase-IE double-blinded
`stady of 179 RRMS patients treated with cither teri-
`flunomide at 7 mg and 14 mg versus placebo showed a
`
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`FUTURE RESEARCH DIRECTIONS IN MULTIPLE SCLEROSIS THERAPIES/G8r -a-Ria oA. ASAI
`123
`
`significant reduction in combined unique active lesions
`seen on MRE in both treatment arms after 36 weeks
`compared with placebo." Phe high-dose group had a
`trend toward reduction of relapses and showed signifi-
`cant differences in their Expanded Disability Status
`Seale (EDS5) score compared with placebo, Ongoing
`trials are investigating whether higher doses are toler-
`ated and mayincrease efficacy, Several otheroral agents
`have shown carly promise in open-label phase-Ha
`studics,
`3-hydroxy-3-methylglutaryl-coenzyme A
`The
`(HMG-CoA) reductase inhibitors called “statins” amel+
`jerate EAE through a variety of immunological mech-
`anismsincluding T-helper type 2 (Th3} cell deviation.7!
`Pilot data with simvastatin showed a 44%reduction of
`Gd-enhancing MRE lesions.*? An Lnmune Tolerance
`Network (ITN)-spensored placebo-cantrolled trial of
`atorvastatin, 80 mg once a day, in patients with clinically
`isolated syndromes (C1Ss) at high risk for conversion to
`MS is in progress. The oral antibiotic minocyeline has
`been shown to have antiinflammatory and possibly
`.
`Wp
`neuroprotective cffects.”” Pilot data from a small study
`of 10 M5 patients suggest an effect in reducing MRI
`activity, and further testing is underway.”" Caution is
`urged regarding widespread off-label use of statins or
`minoeyeline in M5 before definitive clinical trial dara are
`available because it is theoretically possible that these
`drugs could have deleterious effects." A recent epi-
`demiotogical study found that military recruits with
`high-normal vitamin D levels were half as likely to get
`M5 as their counterparts with low-normal or deficient
`levels.?” Because vitamin D not only plays a role in bone
`formation, but is also critical in suppressing interleukin
`(IL}-12 and inducing IL-10, thereby allowing priming
`of Th: cytokine responses, ir could have a role in disease
`onset and even propagation.”* Oral vitamin D supple-
`mentation is now being examined in MS.*" Estriol has
`been shownto have antiinflammatoryproperties in EAE
`and efficacy on active MRI lesions in a pilot study of MS,
`and is also being examined in MS as an adjunet
`to
`glatiramer acetate."
`
`Monacional Antibodies
`The success of the monoclonal antibody natalizumah
`has spurred testing of other monoclonal antibody
`therapies in MS.*? The anti-CD20 (B ceils) monoclo-
`nal Ab (rituximab)
`is
`a chimeric immunoglobulin
`(ig)Gi
`that rapidly depletes circulating B celis after
`ane cycle (two doses taken 2 weeks apart)? Ina recent
`double-blinded placcbo-contrelled phase-[] study, rit-
`uximab was shown to reduce Gd-enhancing lesions by
`91% and reduced the time to first relapse (hazard ratio
`LHR], 0.323; 95% confidence interval [CI], 0.146 to
`0.715). The drag was well
`tolerated, and phase-III
`studics are planned. The rapid MERI
`response at
`
`24 weeks without significant changes in fgG levels
`suggesis that rather than depleting plasma cells and
`lg production, rituximab may inhibit pathogenic B-cell
`evtokines
`(IL-6 and tumor necrosis
`factor alpha
`[TNFa}) or antigen presentation to T cells,*™
`Because B cells are a
`reservoir for viral
`infections
`(Epstein-Barr virus [EBV]} this appraach could theo-
`retically decrease presentation ofviral epitopes that act
`as molecular mimics of myclin basic protcin (MBP).
`Cases of PML have been reported in lymphoma and
`lupus patients treated with rituximab, but chis could be
`related to disease-specific mechanisms or combined
`exposure to other immunosuppressive drugs. As with
`natalizumab (Tysabri), rituximab could promote pre-
`mature release of JC virus—infected Becell precursors
`from the bone marrow.
`Daclizumab is an anu-IL-2 receptor a chain
`(C125) monoclonal antibody (MAb) thar has preven
`efficacy in preventing organ transplantation rejection
`and has shown promise in various autoimmune dis-
`eases.” ‘Two small open-label studics have found a
`reduction in MRI activity and relapses with stable or
`improved EDSS compared with baseline.” Placcho-
`controlled phase-I] dose-ranging studies are in progress.
`Daclizumab docs not appear to deplere CID25-positive
`cells but
`rather actually increases
`the number of
`CD36 + natural killer (NK) cells, which may have reg-
`ulatory functions. **
`The anu-CD52 MAb, alemtuzumab (CAM-
`PATH-1), given in five 20-mg daily doses, causes
`complement-mediated lysis of lymphocytes and pro-
`found and long-lasting depletion of
`iymphocytes
`(1 year). Pilot studies showed abrogation of MRI activity
`and 92% reductionin relapses compared with baseline.”
`A recent study comparing alemtuzumabto thrice weekly
`subcutaneous interferon-B (IFN®)-la showed 2 75%
`reduction of relapses and 65% reduction in the risk for
`progression ofdisability over 2 years. Six patients devel-
`oped idiopathic thrombocytopenia (TP), and one died
`of a brain hemorrhage. Also, a significantly greater
`proportion of patients had thyroid problemsafter 2 years
`of alemtuzumab treatment. These complications suggest
`that aberrant immune responses may occur in immuno-
`genetically predisposed hosts during the immune recon-
`stitution period.”
`Anni-IL-12/23 (P40 chain) MAbs have shown
`efficacy in psoriasis." 1L-12 is a potent ‘Thy-driving
`cytokine produced by monocytes and dendritic cells.
`Laboratory data strongly support its role in Thy-medi-
`ated diseases. The shared use of P40 chain between
`IL-t2 and IL~23 (implicated in ThiL~17 eclis in auto-
`immunity) makes it an attractive target
`in Ms.?
`However, specificity may still be a problem because
`Thy and ThIL-17 cetls are needed to fight off infeerion,
`No clinical data in MS have been reporeed to date, but
`trials are ongoing.
`
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`124
`
`SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 1
`
`2008
`
`
`
`Toward Antigen Specificity and Tolerance
`All of the previousiy described therapics sutter from lack
`ofspecificity for the pathogenic cells char are thought to
`mediate the autonnmune attack in MS. An alternative
`approach has been to selectively antagonize an antigen-
`specthe T-cell clone by targeting its “P-cell
`receptor
`(TCR) directly or indirectly by use of altered peptide
`ligands (APLs).n
`APLs were designed with specific
`amino acid substitutions in key contact residues identi-
`fied in the MBP encephalitogenic peptide such that it
`could still be presented by human teukocyte antigen/
`major histocompatibility complex (HLA/MHC) mole-
`cules and recognized by the TCR specifie for
`that
`peptide, but did not signal and activate the Tcells fully,
`resulting in deviation to a Th» response or even toler-
`ance.
`Initial clinical
`trials resulted in unpredictable
`results with a subtle tend toward improved outcomes
`in low dosages of the APL, but rare patients with
`unexpected discase activation at
`the higher dose?
`Concern regarding epitope spreading as a means ofthe
`immune system recognizing alternative antigens as the
`disease process evolves has also beenraised. Nonetheless,
`interest in this approach persists using lower doses of
`APLs. Another antigen-specific treatment that involves
`loading antigen-presenting cells (APCs) with cocktails
`of relevant myelin peptides and then fixed with ethylene
`carbodiimide have shown promise in animals, and hu-
`man trials are planned."° Several
`trials continue to
`address the possibility of vaccinating patients with irra-
`diated T cells expressing the disease-relevant TCR or
`delivery of myelin peptides as vaccinations to induce
`tolerance to specific T-cell subsets or myelin proteins.
`These approaches presuppose that we knowthe relevant
`antigen(s/TCR that mediates disease in MS, thar the
`disease is
`indeed auteimmune, and that che T-cell
`response is restricied to one or a few antigens. An
`interesting approach being tried in several T-ccll-medi-
`ated diseases involves nonstimulatory anti-CD3 anti-
`bodies, which bind T cells bur induce anergy." These
`have recently been shown to be effective orally in
`amchorating EAI in mice.
`
`Novel Immunomodulators in Preclinical
`Development
`Several novel alternative immunological approaches are
`being developed. Signal transduction inhibitors (for Th,
`cells}, either small molecule inhibitors or small interfer~
`ing (siRNA for T-bet, ameliorates EAE” Similarly,
`there is interest in antagonizing the ThIL-17 specific
`transcription factor ROR-y:."
`Blockade of the outward rectifying potassium
`channel Kv1.3 has been shown to selectively suppress
`T-effector memorycells, which are the costimulation
`independent, CCR?7(— /CD45RA(-—} memory cells
`implicated in MS by several groups and found in MS
`
`ay
`
`33
`brain cissue.
`* Specific Kv1.3 inhibiters are being
`developed that target chronically activated memorycells
`without compromising immediate and acute immune
`responses mediated by naive and central memorycells.
`PLT3 is a tyrosine kinase receptor specifically
`expressed on mature dendritic cells COCs) and perhaps
`microglia, and it is a potential
`target for autoimmune
`diseases.” DCs are professional APCs and mayplay a
`critical role in determining tolerance versus autoimimun-
`itv” CEP701 and other FL‘T3 inhibitors block FL'F3
`signaling and DC maturation, and have been shown to
`ameliorate EAE, presumably through inhibiting antigen
`presentation, but perhaps also by decreasing production
`of pathogenic cytokines and other microglial effector
`molccules.*" Several other approaches designed to inter
`fere with APC function orblock costimulation of Tcells
`are being Investigated, meluding CTLA-4-lg and sai-
`butamol (anti-IT.-12 effeer)27"
`
`STRATEGIES FOR NEUROPROTECTION
`Neuroprotection can be defined as any approach that
`leads to the preservation of neural
`tissue. In MS it is
`thought
`that permanenr disability is associated with
`axomu damage that occurs both as a direct result of the
`acute influx of inflammatory cells during newlesion
`formation, as well as in chromic active lesions character-
`ized by CD68 + macrophages and microglia. However,
`iis also likely that chronically demyelinated axons
`undergo degeneration as a result of loss of trophic
`support of the axons and increased susceptibility to the
`local
`inflammatory environment.’”
`The mechanisms
`underlying this process are fikely multifactorial, hut
`include oxidative stress related to high levels ofnitric
`oxide and its metabolite peroxynitrite, as well as ghita-
`mate-mediated excitotoxicity. Because these processes
`probably occur slowly over manyyears, MS maybe an
`ideal disease in which to initiate therapies directed at
`these CNS processes of degeneration."
`
`Candidate Drugs
`Several Food
`and Drug Administration (FDA)-
`approved drugs have been shownto have neuroprotective
`properties in vitro or in animal models. Minocycline has
`beth antiinflammatory and putative antiapoptotic effects
`in a varietyofdifferent model systems.“? Erythropoietin
`(EPO) has been shown to ameliorate EAE by several
`groups; the recent discovery of EPO receptorsin the brain
`and the possibiliry of dissociating their hematopoietic
`effects from their neuroprotective effects have raised
`hopes that EPO derivatives could be designed for use
`in chronic disease without causing erythracytosis.¢°°*
`Short courses of EPO are being tested in clinical trials
`of stroke, optic neuritis, and transverse myclitis. Several
`epilepsy drugs work by blocking sodium channels, and
`
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`FUTURE RESEARCH DIRECTIONS IN MULTIPLE SCLEROSIS THERAPIES /Ghice N3tRG CA A3R9I
`
`125
`
`thus could prevent influx ofcalcium into axons through
`the sediumcalcium exchanger as well as having indirect
`effects on microglia.” Phenytoin, flecainide, topiramate,
`and Lamictal are ail being investigated in animal models
`of MS.°°"" In addition to cheir antiinflammatoryeffects,
`estrogens have neuroprotective properties and are being
`examined in MS"!
`Antagonists of the glutamate receptor subtypes,
`N-methyl-D-aspartare (NMEDA) and alpha-amino-3-
`hydroxy-5-isoxazoleproptonic acid (AMPA), have been
`shown in models to be neuroprotective and are cunsid-
`ered candidates for MS trials.7°7* Potent NMDA
`antagonism is not tolerated; thus, only weak NMDA
`antagonists,
`such
`as memantine, may be
`feasible.
`AMPA-receptor antagonists have shown cffeacy in
`EAE, have been studied in amyotrophic lateral
`sclerosis (ALS), and could be tricd soon in MS,”°
`Dewnstreamtargets of cell death, such as nitric oxide
`and poly(ADP ribosc}polymerase (PARP), may be
`amenable to intervention; inhibitors of these pathways
`have shown efficacy in animal models of nerve degen-
`eration. 7""*
`Neuroprotection mayalso be mediated by remye-
`lination. Embryonic stemcells offer the ultimate hope of
`reconstinuting CNS tissue, but also the most risk because
`of their potential to differentiate into othertissue types
`or cancer cells as well as obstacles related to their
`isolazion, deliveryto the site of injury, and rejection after
`transplantation. Mesenchymal stem cells and bone mar-
`row-derived hematopoietic stem cells are being cried,
`maynaturally migrate to CNSsites ofinflammation, and
`may actually act by supporting or enhancing resident
`progenitor CNS cells in initiating tissue repair. Stem
`cells can be differentiated into glial restricted precursor
`cells, which may be muchsafer because of their restricted
`lineage potential, bur methods of enhancing differentia-
`tion of these cells into mature myelin-forming oligoden-
`drocytesstill need to be optimized, Partial remyclination
`occurs in the CNS in M5, and pathological studies show
`an
`abundance of oligodendrocyte progenitor
`cells
`(OPCs), but many appear to not successfully differ-
`entiate into mature oligodendracytes. Much emphasis is
`nowbeing placed on identifying the mechanisms respon-
`sible for inhibiting OPC maturation. One promising
`strategythat addresses this problemis the identification
`of LINGO, a natural brake that turns off myelination
`during development. Recently, LINGO antagonists were
`shown to enhance OPC differentiation and to mediare
`myelination of axons in vitro. Remarkably,
`they also
`appear to enhance axon regeneration and thus have the
`potential for dual benefits in MS.””
`
`CONCLUSION
`In the near future it 1s likely thar one or more of the
`promising oral therapies will become available. In addi-
`
`Page 5 of 8
`
`tion, porent ALAbs offer promise for infrequent dosing
`and increased efficacy. The issue of specificity af our
`therapies remains a concern, and all of these successes
`will
`likely come with risks of infection related to im-
`pated function of healthy normal immunecells and/or
`othersystemic side cffeers. Strategies aimed at inducing
`tolerance offer hape for avoiding this nonselective im-
`munosuppression, but these also will ultimately require
`mere knowledge regarding which are the pathogenic
`cells to be tolerized. Neuroprotection and remyclination
`are nowrealistic goals in M5, and promising approaches
`are beginning to be tested. There remains acritical need
`for developing novel clinical trial designs and biomarkers
`of axons and myelin that will allow rapidtesting ofsuch
`agents, much in the way we have been able to screen
`Immunosuppressive drugs using Gd-enhaneed MRI and
`relapses.
`
`ACKNOWLEDGMENTS
`The authors are supported by the National Institutes of
`Health, NS041435 (P.A.C.), National MS Society
`(NMSS) Collaborative Center Award (P.A.C. and
`B.M.G.), NMSS TR-3760-A-3 (P.A.C. and B.M.G.},
`The Naney Davis Foundation (P.A.C.), and The Accel-
`erated CURE project (B.M.G.).
`
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