Future Research Directions in Multiple Sclerosis Therapies

ABSTRACT

The success of presently available injectable immunomodulatory therapies in treating multiple sclerosis has led to heightened interest in finding even more efficacious and better tolerated therapies. Several oral agents have shown efficacy in phase-II clinical trials and are now entering phase-III pivotal trials. In addition, monoclonal antibodies targeting surface receptors on various cells of the peripheral immune system have also shown efficacy in early studies and will soon be entering phase III. All of these approaches target immune molecules that are not specific for multiple sclerosis (MS) and carry inherent risk of infection and systemic side effects. Novel immunotherapies in preclinical or phases I to IIa testing are attempting to more selectively target pathogenic effector cells and thereby block abnormal immune cell activation without compromising normal healthy immune responses. The induction of tolerance to self-proteins continues to be a goal of MS immunotherapy, but as yet has not been accomplished outside of the laboratory. There is increasing awareness of the need to understand and modulate nonclassical immune targets as well as central nervous system degenerative processes. The roles of vitamins, antimicrobials, and hormones continue to be studied. The mechanisms of neurodegeneration in MS are likely multifactorial and include direct damage by T cells and humoral immunity as well as oxidative stress, glutamate-mediated excitotoxicity, and neuronal and oligodendrocyte apoptosis. Neuroprotective drugs that were once only considered for classical degenerative diseases, such as amyotrophic lateral sclerosis and Parkinson's disease, are now being considered in MS.

KEYWORDS

Monoclonal antibodies - immunosuppression - neuroprotection - clinical trials - multiple sclerosis

REFERENCES

• 1 Pittock S J, Lucchinetti C F. The pathology of MS: new insights and potential clinical applications.  Neurologist. 2007;  13(2) 45-56
• 2 Kleinschnitz C, Meuth S G, Kieseier B C, Wiendl H. Immunotherapeutic approaches in MS: update on pathophysiology and emerging agents or strategies 2006.  Endocr Metab Immune Disord Drug Targets. 2007;  7(1) 35-63
• 3 Buttmann M, Rieckmann P. Interferon-beta1b in multiple sclerosis.  Expert Rev Neurother. 2007;  7(3) 227-239
• 4 Wolinsky J S. The use of glatiramer acetate in the treatment of multiple sclerosis.  Adv Neurol. 2006;  98 273-292
• 5 Wingerchuk D M. Multiple sclerosis disease-modifying therapies: adverse effect surveillance and management.  Expert Rev Neurother. 2006;  6(3) 333-346
• 6 Polman C H, O'Connor P W, Havrdova E et al.. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.  N Engl J Med. 2006;  354(9) 899-910
• 7 Berger J R. Natalizumab.  Drugs Today (Barc). 2006;  42(10) 639-655
• 8 O'Connor P. Natalizumab and the role of alpha 4-integrin antagonism in the treatment of multiple sclerosis.  Expert Opin Biol Ther. 2007;  7(1) 123-136
• 9 Ransohoff R M. Natalizumab and PML.  Nat Neurosci. 2005;  8(10) 1275
• 10 Martini S, Peters H, Bohler T, Budde K. Current perspectives on FTY720.  Expert Opin Investig Drugs. 2007;  16(4) 505-518
• 11 Baumruker T, Billich A, Brinkmann V. FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis.  Expert Opin Investig Drugs. 2007;  16(3) 283-289
• 12 Kappos L, Antel J, Comi G et al.. Oral fingolimod (FTY720) for relapsing multiple sclerosis.  N Engl J Med. 2006;  355(11) 1124-1140
• 13 Schilling S, Goelz S, Linker R, Luehder F, Gold R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration.  Clin Exp Immunol. 2006;  145(1) 101-107
• 14 Shear N H. Fulfilling an unmet need in psoriasis: do biologicals hold the key to improved tolerability?.  Drug Saf. 2006;  29(1) 49-66
• 15 Schimrigk S, Brune N, Hellwig K et al.. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.  Eur J Neurol. 2006;  13(6) 604-610
• 16 Jonsson S, Andersson G, Fex T et al.. Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship.  J Med Chem. 2004;  47(8) 2075-2088
• 17 Runstrom A, Leanderson T, Ohlsson L, Axelsson B. Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-beta k.o. and wild type mice.  J Neuroimmunol. 2006;  173(1-2) 69-78
• 18 Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS.  Neurology. 2005;  64(6) 987-991
• 19 Zeyda M, Poglitsch M, Geyeregger R et al.. Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation.  Arthritis Rheum. 2005;  52(9) 2730-2739
• 20 O'Connor P W, Li D, Freedman M S et al.. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses.  Neurology. 2006;  66(6) 894-900
• 21 Youssef S, Stuve O, Patarroyo J C et al.. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.  Nature. 2002;  420(6911) 78-84
• 22 Vollmer T, Key L, Durkalski V et al.. Oral simvastatin treatment in relapsing-remitting multiple sclerosis.  Lancet. 2004;  363(9421) 1607-1608
• 23 Giuliani F, Hader W, Yong V W. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction.  J Leukoc Biol. 2005;  78(1) 135-143
• 24 Metz L M, Zhang Y, Yeung M et al.. Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis.  Ann Neurol. 2004;  55(5) 756
• 25 Miron V E, Rajasekharan S, Jarjour A A, Zamvil S S, Kennedy T E, Antel J P. Simvastatin regulates oligodendroglial process dynamics and survival.  Glia. 2007;  55(2) 130-143
• 26 Yang L, Sugama S, Chirichigno J W et al.. Minocycline enhances MPTP toxicity to dopaminergic neurons.  J Neurosci Res. 2003;  74(2) 278-285
• 27 Munger K L, Levin L I, Hollis B W, Howard N S, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.  JAMA. 2006;  296(23) 2832-2838
• 28 Spach K M, Nashold F E, Dittel B N, Hayes C E. IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis.  J Immunol. 2006;  177(9) 6030-6037
• 29 van der Mei I A, Ponsonby A L, Dwyer T et al.. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia.  J Neurol. 2007;  254 581-590
• 30 Voskuhl R R, Palaszynski K. Sex hormones in experimental autoimmune encephalomyelitis: implications for multiple sclerosis.  Neuroscientist. 2001;  7(3) 258-270
• 31 Cree B. Emerging monoclonal antibody therapies for multiple sclerosis.  Neurologist. 2006;  12(4) 171-178
• 32 Rastetter W, Molina A, White C A. Rituximab: expanding role in therapy for lymphomas and autoimmune diseases.  Annu Rev Med. 2004;  55 477-503
• 33 Cross A H, Stark J L, Lauber J, Ramsbottom M J, Lyons J A. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients.  J Neuroimmunol. 2006;  180(1-2) 63-70
• 34 Stuve O, Cepok S, Elias B et al.. Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis.  Arch Neurol. 2005;  62(10) 1620-1623
• 35 Waldmann T A. Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey.  J Clin Immunol. 2007;  27(1) 1-18
• 36 Rose J W, Watt H E, White A T, Carlson N G. Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody.  Ann Neurol. 2004;  56(6) 864-867
• 37 Bielekova B, Richert N, Howard T et al.. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta.  Proc Natl Acad Sci USA. 2004;  101(23) 8705-8708
• 38 Bielekova B, Catalfamo M, Reichert-Scrivner S et al.. Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis.  Proc Natl Acad Sci USA. 2006;  103(15) 5941-5946
• 39 Coles A J, Cox A, Le Page E et al.. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy.  J Neurol. 2006;  253(1) 98-108
• 40 Loh Y, Oyama Y, Statkute L et al.. Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used.  Blood. 2007;  109(6) 2643-548
• 41 Chong B F, Wong H K. Immunobiologics in the treatment of psoriasis.  Clin Immunol. 2007;  123(2) 129-138
• 42 Gran B, Zhang G X, Rostami A. Role of the IL-12/IL-23 system in the regulation of T-cell responses in central nervous system inflammatory demyelination.  Crit Rev Immunol. 2004;  24(2) 111-128
• 43 Sospedra M, Martin R. Antigen-specific therapies in multiple sclerosis.  Int Rev Immunol. 2005;  24(5-6) 393-413
• 44 Bielekova B, Goodwin B, Richert N et al.. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand.  Nat Med. 2000;  6(10) 1167-1175
• 45 Kappos L, Comi G, Panitch H et al.. Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial.  The Altered Peptide Ligand in Relapsing MS Study Group . Nat Med. 2000;  6(10) 1176-1182
• 46 Smith C E, Miller S D. Multi-peptide coupled-cell tolerance ameliorates ongoing relapsing EAE associated with multiple pathogenic autoreactivities.  J Autoimmun. 2006;  27(4) 218-231
• 47 Fontoura P, Garren H, Steinman L. Antigen-specific therapies in multiple sclerosis: going beyond proteins and peptides.  Int Rev Immunol. 2005;  24(5-6) 415-446
• 48 Ishikawa H, Ochi H, Chen M L, Frenkel D, Maron R, Weiner H L. Inhibition of autoimmune diabetes by oral administration of anti-CD3 monoclonal antibody.  Diabetes. 2007;  56 2103-2109
• 49 Lovett-Racke A E, Rocchini A E, Choy J et al.. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes.  Immunity. 2004;  21(5) 719-731
• 50 Ivanov I I, McKenzie B S, Zhou L et al.. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17 + T helper cells.  Cell. 2006;  126(6) 1121-1133
• 51 Rus H, Pardo C A, Hu L et al.. The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain.  Proc Natl Acad Sci USA. 2005;  102(31) 11094-11099
• 52 Beeton C, Pennington M W, Wulff H et al.. Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases.  Mol Pharmacol. 2005;  67 1369-1381
• 53 Wulff H, Calabresi P A, Allie R et al.. Myelin-reactive effector memory T cell K + channels: a target for multiple sclerosis therapy.  J Clin Invest. 2003;  111 1703-1713
• 54 Whartenby K A, Calabresi P A, McCadden E et al.. Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease.  Proc Natl Acad Sci USA. 2005;  102(46) 16741-16746
• 55 Miller S D, McMahon E J, Schreiner B, Bailey S L. Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis.  Ann N Y Acad Sci. 2007;  1103 179-191
• 56 Manuel S L, Rahman S, Wigdahl B, Khan Z K, Jain P. Dendritic cells in autoimmune diseases and neuroinflammatory disorders.  Front Biosci. 2007;  12 4315-4335
• 57 Khoury S J, Gallon L, Verburg R R et al.. Ex vivo treatment of antigen-presenting cells with CTLA4Ig and encephalitogenic peptide prevents experimental autoimmune encephalomyelitis in the Lewis rat.  J Immunol. 1996;  157(8) 3700-3705
• 58 Makhlouf K, Comabella M, Imitola J, Weiner H L, Khoury S J. Oral salbutamol decreases IL-12 in patients with secondary progressive multiple sclerosis.  J Neuroimmunol. 2001;  117(1-2) 156-165
• 59 Bjartmar C, Trapp B D. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences.  Curr Opin Neurol. 2001;  14(3) 271-278
• 60 McQualter J L, Bernard C C. Multiple sclerosis: a battle between destruction and repair.  J Neurochem. 2007;  100(2) 295-306
• 61 Hauser S L, Oksenberg J R. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration.  Neuron. 2006;  52(1) 61-76
• 62 Maier K, Merkler D, Gerber J et al.. Multiple neuroprotective mechanisms of minocycline in autoimmune CNS inflammation.  Neurobiol Dis. 2007;  25(3) 514-525
• 63 Montero M, Poulsen F R, Noraberg J et al.. Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen-glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures.  Exp Neurol. 2007;  204(1) 106-117
• 64 King C E, Rodger J, Bartlett C, Esmaili T, Dunlop S A, Beazley L D. Erythropoietin is both neuroprotective and neuroregenerative following optic nerve transection.  Exp Neurol. 2007;  205(1) 48-55
• 65 Mi S, Miller R H, Lee X et al.. LINGO-1 negatively regulates myelination by oligodendrocytes.  Nat Neurosci. 2005;  8(6) 745-751
• 66 Craner M J, Damarjian T G, Liu S et al.. Sodium channels contribute to microglia/macrophage activation and function in EAE and MS.  Glia. 2005;  49(2) 220-229
• 67 Bechtold D A, Miller S J, Dawson A C et al.. Axonal protection achieved in a model of multiple sclerosis using lamotrigine.  J Neurol. 2006;  253(12) 1542-1551
• 68 Lo A C, Saab C Y, Black J A, Waxman S G. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo.  J Neurophysiol. 2003;  90(5) 3566-3571
• 69 Offner H, Polanczyk M. A potential role for estrogen in experimental autoimmune encephalomyelitis and multiple sclerosis.  Ann N Y Acad Sci. 2006;  1089 343-372
• 70 Morales L B, Loo K K, Liu H B, Peterson C, Tiwari-Woodruff S, Voskuhl R R. Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis.  J Neurosci. 2006;  26(25) 6823-6833
• 71 Sicotte N L, Voskuhl R R. Onset of multiple sclerosis associated with anti-TNF therapy.  Neurology. 2001;  57(10) 1885-1888
• 72 Kumar S. Memantine: pharmacological properties and clinical uses.  Neurol India. 2004;  52(3) 307-309
• 73 Sarchielli P, Greco L, Floridi A, Floridi A, Gallai V. Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid.  Arch Neurol. 2003;  60(8) 1082-1088
• 74 Bolton C, Paul C. Glutamate receptors in neuroinflammatory demyelinating disease.  Mediators Inflamm. 2006;  2006(2) 93684
• 75 Lipton S A. NMDA receptors, glial cells, and clinical medicine.  Neuron. 2006;  50(1) 9-11
• 76 Pitt D, Werner P, Raine C S. Glutamate excitotoxicity in a model of multiple sclerosis.  Nat Med. 2000;  6(1) 67-70
• 77 Emerit J, Edeas M, Bricaire F. Neurodegenerative diseases and oxidative stress.  Biomed Pharmacother. 2004;  58(1) 39-46
• 78 Kauppinen T M, Suh S W, Genain C P, Swanson R A. Poly(ADP-ribose) polymerase-1 activation in a primate model of multiple sclerosis.  J Neurosci Res. 2005;  81(2) 190-198
• 79 Ji B, Li M, Wu W T et al.. LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury.  Mol Cell Neurosci. 2006;  33(3) 311-320