Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis

Expert Opinion on Investigational Drugs

Volumn 21, Issue 3, 2012, Pages 297-320

  Morren, John A ^a   Galvez Jimenez, Nestor ^a  

^a DEPARTMENT OF COLORECTAL SURGERY   (United States)

Author keywords

ALS; Amyotrophic lateral sclerosis; Disease modifying therapy; Glutamate excitotoxicity; Investigational drugs; Lou Gehrig disease; Motor neuron disease; Neurotrophic factors; Riluzole; Stem cell therapy

Indexed keywords

ACETYLCYSTEINE; ALPHA TOCOPHEROL; ARIMOCLOMOL; BRAIN DERIVED NEUROTROPHIC FACTOR; CEFTRIAXONE; CELECOXIB; CREATINE; DEXPRAMIPEXOLE; DEXTROMETHORPHAN; GABAPENTIN; GLATIRAMER; GRANULOCYTE COLONY STIMULATING FACTOR; LAMOTRIGINE; LITHIUM; MELATONIN; MEMANTINE; MINOCYCLINE; OLESOXIME; OMIGAPIL; PENTOXIFYLLINE; PLACEBO; RILUZOLE; SELEGILINE; TALAMPANEL; TAUROURSODEOXYCHOLIC ACID; THALIDOMIDE; TOPIRAMATE; UBIDECARENONE; UNINDEXED DRUG; XALIPRODEN;

ABDOMINAL PAIN; ADD ON THERAPY; ALANINE AMINOTRANSFERASE BLOOD LEVEL; AMYOTROPHIC LATERAL SCLEROSIS; ANOREXIA; APOPTOSIS; ARTHRALGIA; ASTHENIA; AUTOPHAGY; BACKACHE; BRADYCARDIA; COGNITIVE DEFECT; CONFUSION; CONSTIPATION; DIARRHEA; DISEASE MODEL; DIZZINESS; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG ELIMINATION; DRUG FATALITY; DRUG MEGADOSE; DRUG METABOLISM; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSGEUSIA; DYSPHAGIA; FALL RISK; FALLING; FATIGUE; FEVER; FLU LIKE SYNDROME; FLUSHING; FOOD AND DRUG ADMINISTRATION; FORCED VITAL CAPACITY; GASTROINTESTINAL DISEASE; GASTROINTESTINAL SYMPTOM; HUMAN; HYPERTRANSAMINASEMIA; IMMUNOMODULATION; INFECTION; INJECTION SITE PAIN; INJECTION SITE REACTION; INSOMNIA; INTERSTITIAL LUNG DISEASE; LIVER TOXICITY; MESENCHYMAL STROMA CELL; MULTICENTER STUDY (TOPIC); MULTIPLE CYCLE TREATMENT; NAUSEA; NAUSEA AND VOMITING; NEPHROLITHIASIS; NEUROPROTECTION; NEUTROPENIA; NONHUMAN; PARESTHESIA; PERIPHERAL BLOOD MONONUCLEAR CELL; PRACTICE GUIDELINE; PROTEIN FOLDING; RANDOMIZED CONTROLLED TRIAL (TOPIC); RASH; REVIEW; SEDATION; SIDE EFFECT; SPASTICITY; UREA NITROGEN BLOOD LEVEL; WEAKNESS; WEIGHT GAIN;

AMYOTROPHIC LATERAL SCLEROSIS; ANIMALS; CLINICAL TRIALS AS TOPIC; DRUG DELIVERY SYSTEMS; DRUG DESIGN; DRUGS, INVESTIGATIONAL; GENETIC TESTING; HUMANS; NEUROPROTECTIVE AGENTS; RILUZOLE;

EID: 84856905668     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2012.657303     Document Type: Review

References (159)

1. Bradley WG. Overview of motor neuron disease: classification and nomenclature. Clin Neurosci 1995-1996;3:323-6 (Pubitemid 27052165)
2. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257-68
3. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72:245-56
4. Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet J Rare Dis 2009;4:3
5. Ginsberg G, Lowe S. Cost effectiveness of treatments for amyotrophic lateral sclerosis: a review of the literature. Pharmacoeconomics 2002;20:367-87 (Pubitemid 34712969)
6. Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 1992;326:1464-8
7. Rothstein JD, Van Kammen M, Levey AI, et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995;38:73-84
8. Guo H, Lai L, Butchbach ME, et al. Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. Hum Mol Genet 2003;12:2519-32 (Pubitemid 37220416)
9. Rothstein JD, Patel S, Regan MR, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005;433:73-7 (Pubitemid 40101145)
10. Clinical Trials. Clinical Trial Ceftriaxone in Subjects with ALS, July 2006. Available from: http://clinicaltrials.gov/ct2/results?term=NCT+00349622 [Last accessed 16 October 2011]
11. Van Den Bosch L, Vandenberghe W, Klaassen H, et al. Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons. J Neurol Sci 2000;180:29-34
12. Takuma H, Kwak S, Yoshizawa T, Kanazawa I. Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis. Ann Neurol 1999;46:806-15
13. Blin O, Azulay JP, Desnuelle C, et al. A controlled one-year trial of dextromethorphan in amyotrophic lateral sclerosis. Clin Neuropharmacol 1996;19:189-92 (Pubitemid 26099377)
14. Traynor BJ, Bruijn L, Conwit R, et al. Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology 2006;67:20-7 (Pubitemid 44305456)
15. Pascuzzi RM, Shefner J, Chappell AS, et al. A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2010;11:266-71
16. Clinical trials. Talampanel for Amyotrophic Lateral Sclerosis (ALS), September 2008. Available from: http://clinicaltrials.gov/ct2/results?term= NCT00696332 [Last accessed 16 October 2011]
17. Wang R, Zhang D. Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model. Eur J Neurosci 2005;22:2376-80 (Pubitemid 41653551)
18. de Carvalho M, Pinto S, Costa J, et al. A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2010;11:456-60
19. Miller RG, Moore D, Young LA, et al. Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group. Neurology 1996;47:1383-8 (Pubitemid 26422524)
20. Miller RG, Moore DH II, Gelinas DF, et al. Western ALS Study Group. Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 2001;56:843-8 (Pubitemid 32293584)
21. Ryberg H, Askmark H, Persson LI. A double-blind randomized clinical trial in amyotrophic lateral sclerosis using lamotrigine: effects on CSF glutamate, aspartate, branched-chain amino acid levels and clinical parameters. Acta Neurol Scand 2003;108:1-8 (Pubitemid 36791985)
22. Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. Northeast ALS Consortium. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology 2003;61:456-64 (Pubitemid 37025360)
23. Hartl FU. Molecular chaperones in cellular protein folding. Nature 1996;381:571-9
24. Dierick I, Irobi J, Janssens S, et al. Genetic variant in the HSPB1 promoter region impairs the HSP27 stress response. Hum Mutat 2007;28:830
25. Keizman D, Rogowski O, Berliner S, et al. Low-grade systemic inflammation in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2009;119:383-9
26. Batulan Z, Taylor DM, et al. Induction of multiple heat shock proteins and neuroprotection in a primary culture model of familial amyotrophic lateral sclerosis. Neurobiol Dis 2006;24:213-25 (Pubitemid 44572743)
27. Vigh L, Literati PN, Horvath I, et al. Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nat Med 1997;3:1150-4 (Pubitemid 27444460)
28. Hargitai J, Lewis H, Boros I, et al. Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1. Biochem Biophys Res Commun 2003;307:689-95 (Pubitemid 36944988)
29. Kieran D, Kalmar B, Dick JR, et al. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 2004;10:402-5 (Pubitemid 38508519)
30. Clinical Trials. Phase II/III randomized, placebo-controlled trial of arimoclomol in SOD1 positive familial amyotrophic lateral sclerosis, January 2009. Available from: http://clinicaltrials.gov/ct2/results? term=NCT+00706147 [Last accessed 16 October 2011]
31. Wright PD, Huang M, Weiss A, et al. Screening for inhibitors of the SOD1 gene promoter: pyrimethamine does not reduce SOD1 levels in cell and animal models. Neurosci Lett 2010;482:188-92
32. Lange D. Pyrimethamine as therapy for SOD1 associated FALS: early findings. In 19th International Symposium on ALS/MND, Birmingham, UK, November 3-5, 2008. Amyotroph Lateral Scler 2008;9(Suppl 1):46
33. Urushitani M, Ezzi SA, Julien JP. Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2007;104:2495-500 (Pubitemid 46391424)
34. Takeuchi S, Fujiwara N, Ido A, et al. Induction of protective immunity by vaccination with wild-type apo superoxide dismutase 1 in mutant SOD1 transgenic mice. J Neuropathol Exp Neurol 2010;69:1044-56
35. Gros-Louis F, Soucy G, Lariviere R, Julien JP. Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS. J Neurochem 2010;113:1188-99
36. Raoul C, Abbas-Terki T, Bensadoun JC, et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat Med 2005;11:423-8 (Pubitemid 40562333)
37. Smith RA, Miller TM, Yamanaka K, et al. Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest 2006;116:2290-6 (Pubitemid 44162339)
38. Clinical Trials. Safety, Tolerability, and Activity Study of ISIS SOD1Rx to treat familial amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, January 2010. Available from: http://clinicaltrials.gov/ct2/results? term=NCT +01041222 [Last accessed 16 October 2011]
39. Pasquali L, Longone P, Isidoro C, et al. Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve 2009;40:173-94
40. Kabuta T, Suzuki Y, Wada K. Degradation of amyotrophic lateral sclerosis-linked mutant Cu,Zn-superoxide dismutase proteins by macroautophagy and the proteasome. J Biol Chem 2006;281:30524-33 (Pubitemid 44582109)
41. Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008;105:2052-7 (Pubitemid 351439463)
42. Lum JJ, DeBerardinis RJ, Thompson CB. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 2005;6:439-48 (Pubitemid 40780556)
43. Sarkar S, Rubinsztein DC. Small molecule enhancers of autophagy for neurodegenerative diseases. Mol Biosyst 2008;4:895-901
44. Aggarwal SP, Zinman L, Simpson E, et al. Northeast and Canadian Amyotrophic Lateral Sclerosis consortia. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010;9:481-8
45. Chio A, Borghero G, Calvo A, et al. Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial; LITALS Study Group. Neurology 2010;75:619-25
46. Miller RG, Moore DH, Forshew DA, et al. WALS Study Group. Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology 2011;77:973-9
47. Zhang L, Yu J, Pan H, et al. Small molecule regulators of autophagy identified by an image-based high-throughput screen. Proc Natl Acad Sci USA 2007;104:19023-8
48. Williams A, Sarkar S, Cuddon P, et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nat Chem Biol 2008;4: 295-05
49. Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 2009;457:981-9
50. Pawlyk AC, Cassel JA, Reitz AB. Current nervous system related drug targets for the treatment of amyotrophic lateral sclerosis. Curr Pharm Des 2010;16:2053-73.
51. Gordon PH, Moore DH, Gelinas DF, et al. Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology 2004;62:1845-7 (Pubitemid 38661748)
52. Gordon PH, Moore DH, Miller RG, et al. Western ALS Study Group. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007;6:1045-53 (Pubitemid 350116691)
53. Waldmeier PC, Boulton AA, Cools AR, et al. Neurorescuing effects of the GAPDH ligand CGP 3466B. J Neural Transm Suppl 2000;60:197-14
54. Groeneveld GJ, van Muiswinkel FL, de Leeuw van Weenen J, et al. CGP 3466B has no effect on disease course of (G93A) mSOD1 transgenic mice. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5:220-5 (Pubitemid 40125188)
55. Miller R, Bradley W, Cudkowicz M, et al. TCH346 Study Group. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 2007;69:776-84 (Pubitemid 47300935)
56. Mioduszewska B, Jaworski J, Kaczmarek L. Inducible cAMP early repressor (ICER) in the nervous system-a transcriptional regulator of neuronal plasticity and programmed cell death. J Neurochem 2003;87:1313-20 (Pubitemid 38020566)
57. Meininger V, Asselain B, Guillet P, et al. Pentoxifylline European Group. Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial. Neurology 2006;66:88-92 (Pubitemid 43739598)
58. Castro RE, Sola S, Ramalho RM, et al. The bile acid tauroursodeoxycholic acid modulates phosphorylation and translocation of bad via phosphatidylinositol 3-kinase in glutamate-induced apoptosis of rat cortical neurons. J Pharmacol Exp Ther 2004;311:845-52 (Pubitemid 39391575)
59. Clinical Trials. Efficacy and tolerability of tauroursodeoxycholic acid in amyotrophic lateral sclerosis, June 2008. Available from: http://clinicaltrials.gov/ct2/results?term=NCT00877604 [Last accessed 16 October 2011]
60. Clinical Trials. Cistanche total glycosides for amyotrophic lateral sclerosis: a randomized control trial (RCT) study assessing clinical response, January 2008. Available from: http://clinicaltrials.gov/ct2/results?term= NCT00753571 [Last accessed 16 October 2011]
61. Sasaki S, Iwata M. Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis. Neurology 1996;47:535-40 (Pubitemid 26324056)
62. Atsumi T, Miyatake T. Morphometry of the degenerative process in the hypoglossal nerves in amyotrophic lateral sclerosis. Acta Neuropathol 1987;73:25-31 (Pubitemid 17046130)
63. Dupuis L, di Scala F, Rene F, et al. Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. FASEB J 2003;17:2091-3
64. Israelson A, Arbel N, Da Cruz S, et al. Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron 2010;67:575-87
65. Shefner JM, Cudkowicz ME, Schoenfeld D, et al. NEALS Consortium. A clinical trial of creatine in ALS. Neurology 2004;63:1656-61 (Pubitemid 39507584)
66. Clinical Trials. Safety and Efficacy Study of Creatine and Tamoxifen in Volunteers With Amyotrophic Lateral Sclerosis (ALS), March 2011. Available from: http://clinicaltrials.gov/ct2/results? term=NCT01257581 [Last accessed 16 October 2011]
67. Bordet T, Buisson B, Michaud M, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther 2007;322:709-20 (Pubitemid 47105813)
68. Trophos announces results of phase 3 study of olesoxime in Amyotrophic Lateral Sclerosis. Trophos: Press Release, December 2011. Available from: http://www.trophos.com/news/pr20111213.htm [Last accessed 5 January 2012]
69. Danzeisen R, Schwalenstoecker B, Gillardon F, et al. Targeted antioxidative and neuroprotective properties of the dopamine agonist pramipexole and its nondopaminergic enantiomer SND919CL2x [(+)2-amino-4,5,6,7-tetrahydro-6- Lpropylamino-benzathiazole dihydrochloride]. J Pharmacol Exp Ther 2006;316:189-99 (Pubitemid 41832596)
70. Clinical Trials. Phase 3 Study of Dexpramipexole in ALS, March 2011. Available from: http://clinicaltrials.gov/ct2/results?term=NCT01281189 [Last accessed 16 October 2011]
71. Tan DX, Reiter RJ, Manchester LC, et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002;2:181-97
72. Wang X, Figueroa BE, Stavrovskaya IG, et al. Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke 2009;40:1877-85
73. Weishaupt JH, Bartels C, Polking E, et al. Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res 2006;41:313-23 (Pubitemid 44498217)
74. Desnuelle C, Dib M, Garrel C, Favier A. A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotroph Lateral Scler Other Motor Neuron Disord 2001;2:9-18 (Pubitemid 32472143)
75. Kwiecinski H, Janik P, Jamrozik Z, Opuchlik A. The effect of selegiline and vitamin E in the treatment of ALS: an open randomized clinical trials. Neurol Neurochir Pol 2001;35(1 Suppl):101-6
76. Andreassen OA, Dedeoglu A, Klivenyi P, et al. N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport 2000;11:2491-3 (Pubitemid 30622295)
77. Henderson JT, Javaheri M, Kopko S, Roder JC. Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-L-cysteine. J Neurosci 1996;16:7574-82 (Pubitemid 26389697)
78. Louwerse ES, Weverling GJ, Bossuyt PM, et al. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol 1995;52:559-64
79. Sohmiya M, Tanaka M, Suzuki Y, et al. An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients. J Neurol Sci 2005;228:49-53 (Pubitemid 39656494)
80. Beal MF. Coenzyme Q10 as a possible treatment for neurodegenerative diseases. Free Radic Res 2002;36:455-60 (Pubitemid 35154095)
81. Kaufmann P, Thompson JL, Levy G, et al. QALS Study Group. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol 2009;66:235-44
82. Crow JP, Calingasan NY, Chen J, et al. Manganese porphyrin given at symptom onset markedly extends survival of ALS mice. Ann Neurol 2005;58:258-65 (Pubitemid 41098883)
83. Orrell RW. AEOL-10150 (Aeolus). Curr Opin Investig Drugs 2006;7:70-80
84. Siciliano G, Carlesi C, Pasquali L, et al. Clinical trials for neuroprotection in ALS. CNS Neurol Disord Drug Targets 2010;9:305-13.
85. Vyth A, Timmer JG, Bossuyt PM, et al. Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants. J Neurol Sci 1996;139(Suppl):99-103
86. Almer G, Guegan C, Teismann P, et al. Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis. Ann Neurol 2001;49:176-85 (Pubitemid 32157993)
87. Maihofner C, Probst-Cousin S, Bergmann M, et al. Expression and localization of cyclooxygenase-1 and-2 in human sporadic amyotrophic lateral sclerosis. Eur J Neurosci 2003;18:1527-34 (Pubitemid 37215106)
88. Kelley KA, Ho L, Winger D, et al. Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2. Am J Pathol 1999;155:995-04
89. Iadecola C, Niwa K, Nogawa S, et al. Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartatemediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci USA 2001;98:1294-9 (Pubitemid 32121226)
90. Drachman DB, Frank K, Dykes-Hoberg M, et al. Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann Neurol 2002;52:771-8 (Pubitemid 35403187)
91. Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 2006;60:22-31
92. Clinical Trials. Safety and tolerability of anakinra in combination with riluzol in amyotrophic lateral sclerosis, February 2011. Available from: http://clinicaltrials. gov/ct2/results?term=NCT01277315 [Last accessed 16 October 2011]
93. Holmøy T. T cells in amyotrophic lateral sclerosis. Eur J Neurol 2008;15:360-6 (Pubitemid 351424091)
94. Beers DR, Henkel JS, Zhao W, et al. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci USA 2008;105:15558-63
95. Habisch HJ, Schwalenstocker B, Danzeisen R, et al. Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS. Exp Neurol 2007;206:288-95 (Pubitemid 47094773)
96. Gordon PH, Doorish C, Montes J, et al. Randomized controlled phase II trial of glatiramer acetate in ALS. Neurology 2006;66:1117-19 (Pubitemid 44044808)
97. Meininger V, Drory VE, Leigh PN, et al. Glatiramer acetate has no impact on disease progression in ALS at 40 mg/day: a double-blind, randomized, multicentre, placebo-controlled trial. Amyotroph Lateral Scler 2009;10:378-83
98. Papadimitriou D, Le Verche V, Jacquier A, et al. Inflammation in ALS and SMA: sorting out the good from the evil. Neurobiol Dis 2010;37:493-502
99. Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. Minocycline delays disease onset and mortality in a transgenic model of ALS. Neuroreport 2002;13:1067-70 (Pubitemid 34587742)
100. Kriz J, Nguyen MD, Julien JP. Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2002;10:268-78 (Pubitemid 35217580)
101. Franks ME, Macpherson GR, Figg WD. Thalidomide. Lancet 2004;363:1802-11 (Pubitemid 38698386)
102. Kiaei M, Petri S, Kipiani K, et al. Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurosci 2006;26:2467-73 (Pubitemid 44699007)
103. Clinical Trials. Phase II study using thalidomide for the treatment of ALS, February 2005. Available from: http://clinicaltrials.gov/ct2/results?term= NCT00140452 [Last accessed 16 October 2011]
104. A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III). Neurology 1999;52(7):1427-33
105. Bongioanni P, Reali C, Sogos V. Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2004(3):CD004302
106. Mitchell JD, Wokke JH, Borasio GD. Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2007(4):CD002064
107. Mizisin AP, DiStefano PS, Liu X, et al. Decreased accumulation of endogenous brain-derived neurotrophic factor against constricting sciatic nerve ligatures in streptozotocin-diabetic and galactose-fed rats. Neurosci Lett 1999;263:149-52 (Pubitemid 29158950)
108. Seeburger JL, Springer JE. Experimental rationale for the therapeutic use of neurotrophins in amyotrophic lateral sclerosis. Exp Neurol 1993;124:64-72 (Pubitemid 24041753)
109. Kalra S, Genge A, Arnold DL. A prospective, randomized, placebo-controlled evaluation of corticoneuronal response to intrathecal BDNF therapy in ALS using magnetic resonance spectroscopy: feasibility and results. Amyotroph Lateral Scler Other Motor Neuron Disord 2003;4:22-6 (Pubitemid 36636909)
110. Beck M, Flachenecker P, Magnus T, et al. Autonomic dysfunction in ALS: a preliminary study on the effects of intrathecal BDNF. Amyotroph Lateral Scler Other Motor Neuron Disord 2005;6:100-3 (Pubitemid 40903539)
111. Vincent AM, Mobley BC, Hiller A, Feldman EL. IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis 2004;16:407-16 (Pubitemid 38765100)
112. Anlar B, Sullivan KA, Feldman EL. Insulin-like growth factor-I and central nervous system development. Horm Metab Res 1999;31:120-5 (Pubitemid 29169485)
113. Torres-Aleman I, Barrios V, Berciano J. The peripheral insulin-like growth factor system in amyotrophic lateral sclerosis and in multiple sclerosis. Neurology 1998;50:772-6
114. Hosback S, Hardiman O, Nolan CM, et al. Circulating insulin-like growth factors and related binding proteins are selectively altered in amyotrophic lateral sclerosis and multiple sclerosis. Growth Horm IGF Res 2007;17:472-9 (Pubitemid 350056416)
115. Lai EC, Felice KJ, Festoff BW, et al. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology 1997;49:1621-30 (Pubitemid 28015128)
116. Borasio GD, Robberecht W, Leigh PN, et al. A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurology 1998;51:583-6 (Pubitemid 28406343)
117. Sorenson EJ, Windbank AJ, Mandrekar JN, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 2008;71:1770-5
118. Oosthuyse B, Moons L, Storkebaum E, et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 2001;28:131-8 (Pubitemid 32538057)
119. Zheng C, Nennesmo I, Fadeel B, Henter JI. Vascular endothelial growth factor prolongs survival in a transgenic mouse model of ALS. Ann Neurol 2004;56:564-7 (Pubitemid 39319348)
120. Storkebaum E, Lambrechts D, Dewerchin M, et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 2005;8:85-92 (Pubitemid 41236736)
121. Clinical Trial. A Safety and tolerability study of intracerebroventricular administration of sNN0029 to patients with amyotrophic lateral sclerosis, December 2008. Available from: http://clinicaltrials.gov/ct2/ results?term=NCT +00800501 [Last accessed 16 October 2011]
122. Pitzer C, Kruger C, Plaas C, et al. Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis. Brain 2008;131:3335-47
123. Chio A, Mora G, La Bella V, et al. STEMALS Study Group. Repeated courses of granulocyte colony-stimulating factor in amyotrophic lateral sclerosis: clinical and biological results from a prospective multicenter study. Muscle Nerve 2011;43:189-95
124. Zhang Y, Wang L, Fu Y, et al. Preliminary investigation of effect of granulocyte colony stimulating factor on amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2009;10:430-1
125. Nefussy B, Artamonov I, Deutsch V, et al. Recombinant human granulocyte-colony stimulating factor administration for treating amyotrophic lateral sclerosis: a pilot study. Amyotroph Lateral Scler 2010;11:187-93
126. Fournier J, Steinberg R, Gauthier T, et al. Protective effects of SR 57746A in central and peripheral models of neurodegenerative disorders in rodents and primates. Neuroscience 1993;55:629-41 (Pubitemid 23226109)
127. Lacomblez L, Bensimon G, Douillet P, et al. Xaliproden in amyotrophic lateral sclerosis: early clinical trials. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5:99-106 (Pubitemid 39545337)
128. Meininger V, Bensimon G, Bradley WR, et al. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotroph Lateral Scler OtherMotor Neuron Disord 2004;5:107-17 (Pubitemid 39545338)
129. Gao J, Coggeshall RE, Chung JM, et al. Functional motoneurons develop from human neural stem cell transplants in adult rats. Neuroreport 2007;18:565-9 (Pubitemid 46594916)
130. Hall ED, Oostveen JA, Gurney ME. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 1998;23:249-56 (Pubitemid 28259722)
131. Xu L, Ryugo DK, Pongstaporn T, et al. Human neural stem cell grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. J Comp Neurol 2009;514:297-309
132. Corti S, Nizzardo M, Nardini M, et al. Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a model of amyotrophic lateral sclerosis. Hum Mol Genet 2010;19:3782-96
133. de Filippis L. Neural stem cell-mediated therapy for rare brain diseases: perspectives in the near future for LSDs and MNDs. Histol Histopathol 2011;26:1093-1109
134. Gamez J, Carmona F, Raguer N, et al. Cellular transplants in amyotrophic lateral sclerosis patients: an observational study. Cytotherapy 2010;12:669-77
135. Blanquer M, Perez Espejo MA, Iniesta F, et al. Bone marrow stem cell transplantation in amyotrophic lateral sclerosis: technical aspects and preliminary results from a clinical trial. Methods Find Exp Clin Pharmacol 2010;32:31-7
136. Deda H, Inci MC, Kurekci AE, et al. Treatment of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up. Cytotherapy 2009;11:18-25
137. Martinez HR, Gonzalez-Garza MT, Moreno-Cuevas JE, et al. Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients. Cytotherapy 2009;11:26-34
138. Clinical Trial. A Study of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS), March 2010. Available from: http://clinicaltrials.gov/ ct2/results?term=NCT +01089010 [Last accessed 16 October 2011]
139. Shefner J. Rationale and design for Phase IIa Study evaluating CK-2017357, a novel activator of fast skeletal muscle, in patients with ALS. 21st International Symposium on ALS/MND; 11-13 December 2010; Orlando, FL, USA
140. Clinical Trials. A Safety, tolerability, pharmacokinetic and pharmacodynamic study of ACE-031 in healthy postmenopausal women, August 2009. Available from: http://clinicaltrials.gov/ct2/results?term=NCT00952887 [Last accessed 16 October 2011]
141. Cadena SM, Tomkinson KN, Monnell TE, et al. Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type. J Appl Physiol 2010;109:635-42
142. Borgstein NG, Barger R, Yang Y, et al. A phase I multiple ascending dose study to assess the pharmacodynamic effects of ACE-031, an inhibitor of negative muscle regulators in healthy volunteers Poster P3.18. 15th International Congress of the World Muscle Society; 12-16 October 2010; Kunamoto, Japan
143. Jokic N, Gonzalez de Aguilar JL, Pradat PF, et al. Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity. Ann Neurol 2005;57:553-6 (Pubitemid 40471166)
144. Jokic N, Gonzalez de Aguilar JL, Dimou L, et al. The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model. EMBO Rep 2006;7:1162-7 (Pubitemid 44660574)
145. Liu BP, Cafferty WB, Budel SO, Strittmatter SM. Extracellular regulators of axonal growth in the adult central nervous system. Philos Trans R Soc Lond B Biol Sci 2006;361:1593-10
146. Clinical Trial. First time in human study of GSK1223249 in amyotrophic lateral sclerosis, May 2009. Available from: http://clinicaltrials.gov/ct2/ results? term=NCT+00875446 [Last accessed 16 October 2011]
147. Rutkove S. Electrical impedance myography as a biomarker for ALS. Lancet Neurol 2009;8:226; author reply 227
148. Yarn JC. Disappointments in medicine: lack of effective treatment for neurological disorders like ALS. Can Fam Physician 2011; 57:333
149. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 1994;330:585-91. (Pubitemid 24065791)
150. Lacomblez L, Bensimon G, Leigh PN, et al. Dose-ranging study of riluzole
151. Riviere M, Meininger V, Zeisser P, Munsat T. An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole. Arch Neurol 1998;55:526-8. (Pubitemid 28182699)
152. Bensimon G, Lacomblez L, Delumeau JC, et al. Riluzole/ALS Study Group II. A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. J Neurol 2002;249:609-15 (Pubitemid 34516368)
153. Mitchell JD, O'brien MR, Joshi M. Audit of outcomes in motor neuron disease (MND) patients treated with riluzole. Amyotroph Lateral Scler 2006;7:67-71 (Pubitemid 43878826)
154. Traynor BJ, Alexander M, Corr B, et al. An outcome study of riluzole in amyotrophic lateral sclerosis-a population-based study in Ireland, 1996-2000. J Neurol 2003;250:473-9 (Pubitemid 36459755)
155. Phase 2 study of talampanel for the treatment of amyotrophic lateral sclerosis (ALS). Monthly Prescribing Reference. News Drugs in the Pipeline, May 2010. Available from: http://www.empr.com/phase-2-study-of-talampanel-for- thetreatment-of-amyotrophic-lateral-sclerosisals/article/170351/[Last accessed 5 January 2012]
156. Biogen Idec and Knopp Neurosciences Announce License Agreement for Late-Stage ALS Drug Candidate (dexpramipexole). Biogen Idec. Press Release Details, August 2010. Available from: http://www.biogenidec.com/PRESS-RELEASE- DETAILS.aspx? ID=5981&ReqId=1461011 [Last accessed 16 October 2011]
157. Amyotrophic Lateral Sclerosis (ALS) AEOL10150. Center Watch. New Medical Therapies, December 2007. Available from: http://www.centerwatch. com/clinical-trials/results/new-therapies/nmt-details.aspx?CatID=160 [Last accessed 16 October 2011]
158. Stommel EW, Cohen JA, Fadul CE, et al. Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotroph Lateral Scler 2009;10:393-404
159. Meyer T, Maier A, Borisow N, et al. Thalidomide causes sinus bradycardia in ALS. J Neurol 2008;255:587-91