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Experimental trials in amyotrophic lateral sclerosis: a review of recently completed, ongoing and planned trials using existing and novel drugs

, MD & , MD

Bibliography

  • Chuang DM, Chen RW, Chalecka-Franaszek E, et al. Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord 2002;4:129-36
  • Rametti A, Esclaire F, Yardin C, et al. Lithium down-regulates tau in cultured cortical neurons: a possible mechanism of neuroprotection. Neurosci Lett 2008;434:93-8
  • Hashimoto R, Takei N, Shimazu K, et al. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity. Neuropharmacology 2002;43:1173-9
  • Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008;105:2052-7
  • Fornai F, Longone P, Ferrucci M, et al. Autophagy and amyotrophic lateral sclerosis: the multiple roles of lithium. Autophagy 2008;4:527-30
  • Sarkar S, Floto R, Berger Z, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 2005;170:1101-11
  • Aggarwal S, Zinman L, Simpson E, et al. 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
  • Chiò A, Borghero G, Calvo A, et al. Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology 2010;75:619-25
  • Miller R, Moore D, Forshew D, et al. Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. Neurology 2011;77:973-9
  • Wicks P, Vaughan T, Massagli M, Heywood J. Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm. Nat Biotechnol 2011;29:411-14
  • Verstraete E, Veldink J, Huisman M, et al. Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial. J Neurol Neurosurg Psychiatry 2012;83:557-64
  • Group UK-LS. Morrison K, Dhariwal S, Hornabrook R, et al. Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013;12:339-45
  • Hirata A, Nakamura R, Kwak S, et al. AMPA receptor-mediated slow neuronal death in the rat spinal cord induced by long-term blockade of glutamate transporters with THA. Brain Res 1997;771:37-44
  • Legay V, Deleage C, Beaulieux F, et al. Impaired glutamate uptake and EAAT2 downregulation in an enterovirus chronically infected human glial cell line. Eur J Neurosci 2003;17:1820-8
  • Rothstein J, Patel S, Regan M, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005;433:73-7
  • Rothstein J, Van Kammen M, Levey A, et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995;38:73-84
  • Maragakis N, Dykes-Hoberg M, Rothstein J. Altered expression of the glutamate transporter EAAT2b in neurological disease. Ann Neurol 2004;55:469-77
  • Van Den Bosch L, Robberecht W. Crosstalk between astrocytes and motor neurons: what is the message? Exp Neurol 2008;211:1-6
  • Canton T, Böhme G, Boireau A, et al. RPR 119990, a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: synthesis, pharmacological properties, and activity in an animal model of amyotrophic lateral sclerosis. J Pharmacol Exp Ther 2001;299:314-22
  • Van Damme P, Leyssen M, Callewaert G, et al. The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. Neurosci Lett 2003;343:81-4
  • Chappell A, Sander J, Brodie M, et al. A crossover, add-on trial of talampanel in patients with refractory partial seizures. Neurology 2002;58:1680-2
  • Greene I, Lee E-Y, Prow N, et al. Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection. Proc Natl Acad Sci USA 2008;105:3575-80
  • Pascuzzi R, Shefner J, Chappell A, et al. A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2010;11:266-71
  • Nizzardo M, Nardini M, Ronchi D, et al. Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms. Exp Neurol 2011;229:214-25
  • Miller B, Dorner J, Shou M, et al. Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington’s disease phenotype in the R6/2 mouse. Neuroscience 2008;153:329-37
  • Melzer N, Meuth S, Torres-Salazar D, et al. A beta-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis. PLoS One 2008;3:e3149
  • Thöne-Reineke C, Neumann C, Namsolleck P, et al. The beta-lactam antibiotic, ceftriaxone, dramatically improves survival, increases glutamate uptake and induces neurotrophins in stroke. J Hypertens 2008;26:2426-35
  • Rothstein J, Kuncl R. Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity. J Neurochem 1995;65:643-51
  • Carreer R, Deby-Dupont G, Deby C, et al. Oxidant-scavenging activities of beta-lactam agents. Eur J Clin Microbiol Infect Dis 1998;17:43-6
  • Berry J, Shefner J, Conwit R, et al. Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis. PLoS One 2013;8:e61177
  • Miller RG, Block G, Gopalakrishnam V, McGrath M; Grp NPPIS. Phase II Trial of NP001 in ALS. Ann Neurol 2013;74:S95-5
  • Neuraltus. Neuraltus Pharmaceuticals’ NP001 Phase 2 Results Highlighted at the 24th International Symposium on ALS/MND [online]. Available from: http://www.neuraltus.com/pages/news_rel12_09_13.html [Accessed 6 June 2014]
  • Renton A, Chiò A, Traynor B. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 2014;17:17-23
  • Rothstein J. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol 2009;65(Suppl 1):9
  • Miller T, Smith R, Kordasiewicz H, Kaspar B. Gene-targeted therapies for the central nervous system. Arch Neurol 2008;65:447-51
  • Bennett C, Swayze E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 2010;50:259-93
  • Smith R, Miller T, Yamanaka K, et al. Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest 2006;116:2290-6
  • Miller T, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12:435-42
  • Alavian K, Dworetzky S, Bonanni L, et al. Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency. Brain Res 2012;1446:1-11
  • 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
  • Bozik M, Mather J, Kramer W, et al. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. J Clin Pharmacol 2011;51:1177-85
  • Cudkowicz M, Bozik M, Ingersoll E, et al. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med 2011;17:1652-6
  • Cudkowicz M, van den Berg L, Shefner J, et al. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol 2013;12:1059-67
  • Berry J, Miller R, Moore D, et al. The Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:162-8
  • 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
  • Kalmar B, Burnstock G, Vrbová G, et al. Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats. Exp Neurol 2002;176:87-97
  • Kalmar B, Lu CH, Greensmith L. The role of heat shock proteins in Amyotrophic Lateral Sclerosis: the therapeutic potential of Arimoclomol. Pharmacol Ther 2014;141:40-54
  • Kieran D, Kalmar B, Dick J, et al. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 2004;10:402-5
  • Cudkowicz M, Shefner J, Simpson E, et al. Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. Muscle Nerve 2008;38:837-44
  • Lee K, Yoon D, Chung MA, et al. Neuroprotective effects of mexiletine on motor evoked potentials in demyelinated rat spinal cords. Neurosci Res 2010;67:59-64
  • Ates O, Cayli S, Gurses I, et al. Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injury. J Clin Neurosci 2007;14:658-65
  • Ates O, Cayli S, Gurses I, et al. Do sodium channel blockers have neuroprotective effect after onset of ischemic insult? Neurol Res 2007;29:317-23
  • Fritz E, Izaurieta P, Weiss A, et al. Mutant SOD1-expressing astrocytes release toxic factors that trigger motoneuron death by inducing hyperexcitability. J Neurophysiol 2013;109:2803-14
  • Dupuis L, Gonzalez de Aguilar JL, di Scala F, et al. Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis. Neurobiol Dis 2002;10:358-65
  • 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
  • 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
  • Meininger V, Pradat P-F, Corse A, et al. Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial. PLoS One 2014;9:e97803
  • Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002;296:346-9
  • Cohen J, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010;362:402-15
  • Kano O, Beers D, Henkel J, Appel S. Peripheral nerve inflammation in ALS mice: cause or consequence. Neurology 2012;78:833-5
  • Gowing G, Lalancette-Hébert M, Audet JN, et al. Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase. Exp Neurol 2009;220:267-75
  • Butovsky O, Siddiqui S, Gabriely G, et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 2012;122:3063-87
  • Speiser Z, Mayk A, Eliash S, Cohen S. Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat. J Neural Transm 1999;106:593-606
  • Huang W, Chen Y, Shohami E, Weinstock M. Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse. Eur J Pharmacol 1999;366:127-35
  • Stefanova N, Poewe W, Wenning G. Rasagiline is neuroprotective in a transgenic model of multiple system atrophy. Exp Neurol 2008;210:421-7
  • Waibel S, Reuter A, Malessa S, et al. Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. J Neurol 2004;251:1080-4
  • Olanow C, Rascol O. The delayed-start study in Parkinson disease: can’t satisfy everyone. Neurology 2010;74:1149-50
  • Ahlskog J, Uitti R. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology 2010;74:1143-8
  • Nefussy B AI, Drory VE. Treatment with rasagiline in patients with amyotrophic lateral sclerosis. Ann Neurol 2007;62:S60-0
  • Swerdlow R, Parks J, Pattee G, Parker W. Role of mitochondria in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:185-90
  • Siklós L, Engelhardt J, Harati Y, et al. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis. Ann Neurol 1996;39:203-16
  • Bowling A, Schulz J, Brown R, Beal M. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 1993;61:2322-5
  • Fujita K, Yamauchi M, Shibayama K, et al. Decreased cytochrome c oxidase activity but unchanged superoxide dismutase and glutathione peroxidase activities in the spinal cords of patients with amyotrophic lateral sclerosis. J Neurosci Res 1996;45:276-81
  • Wang YX, Moore D, Katz J, et al. A multicenter screening trial of the safety and efficacy of rasagiline in people with ALS. Neurology 2013;80:S36.006
  • Macchi YW Z, Moore D, et al. Possible mitochondrial target engagement in an open-label trial of rasagiline for ALS. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:230
  • Traub R, Mitsumoto H, Rowland L. Research advances in amyotrophic lateral sclerosis, 2009 to 2010. Curr Neurol Neurosci Rep 2011;11:67-77
  • Gordon P. Amyotrophic lateral sclerosis: an update for 2013 clinical features, pathophysiology, management and therapeutic trials. Aging Dis 2013;4:295-310
  • Xu L, Yan J, Chen D, et al. Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 2006;82:865-75
  • Xu L, Ryugo D, 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
  • Xu L, Shen P, Hazel T, et al. Dual transplantation of human neural stem cells into cervical and lumbar cord ameliorates motor neuron disease in SOD1 transgenic rats. Neurosci Lett 2011;494:222-6
  • Xu L, Mahairaki V, Koliatsos V. Host induction by transplanted neural stem cells in the spinal cord: further evidence for an adult spinal cord neurogenic niche. Regen Med 2012;7:785-97
  • Glass J, Boulis N, Johe K, et al. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells 2012;30:1144-51
  • Feldman E, Boulis N, Hur J, et al. Intraspinal neural stem cell injections in ALS subjects: phase I trial outcomes. Ann Neurol 2014;75:363-73
  • Boulis N, Federici T, Glass J, et al. Translational stem cell therapy for amyotrophic lateral sclerosis. Nat Rev Neurol 2011;8:172-6
  • Lunn J, Sakowski S, Federici T, et al. Stem cell technology for the study and treatment of motor neuron diseases. Regen Med 2011;6:201-13
  • Lunn J, Sakowski S, Feldman E. Stem cell therapies for amyotrophic lateral sclerosis: recent advances and prospects for the future. Stem Cells 2014;32:1099-109
  • Knippenberg S, Thau N, Dengler R, et al. Intracerebroventricular injection of encapsulated human mesenchymal cells producing glucagon-like peptide 1 prolongs survival in a mouse model of ALS. PLoS One 2012;7:e36857
  • Minguell J, Allers C, Lasala G. Mesenchymal stem cells and the treatment of conditions and diseases: the less glittering side of a conspicuous stem cell for basic research. Stem Cells Dev 2013;22:193-203
  • Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010;67:1187-94
  • Gordon P, Moore D, Miller R, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007;6:1045-53
  • A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III). Neurology 1999;52:1427-33
  • A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. ALS CNTF Treatment Study Group. Neurology 1996;46:1244-9
  • Sorenson E, Windbank A, Mandrekar J, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 2008;71:1770-5
  • Ochs G, Penn R, York M, et al. A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:201-6
  • Shefner J, Watson M, Simionescu L, et al. Multipoint incremental motor unit number estimation as an outcome measure in ALS. Neurology 2011;77:235-41
  • Shefner J, Cudkowicz M, Zhang H, Northeast ALSC. The use of statistical MUNE in a multicenter clinical trial. Muscle Nerve 2004;30:463-9
  • Saccà F, Quarantelli M, Rinaldi C, et al. A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results. J Neurol 2012;259:132-8
  • Duning T, Schiffbauer H, Warnecke T, et al. G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis: a pilot trial. PLoS One 2011;6:e17770
  • Rutkove S, Caress J, Cartwright M, et al. Electrical impedance myography as a biomarker to assess ALS progression. Amyotroph Lateral Scler 2012;13:439-45

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