Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Are immunotherapies for Huntington’s disease a realistic option?

Abstract

There is compelling evidence that the pathophysiology of many neurodegenerative diseases includes dysregulation of the immune system, with some elements that precede disease onset. However, if these alterations are prominent, why have clinical trials targeting this system failed to translate into long-lasting meaningful benefits for patients? This review focuses on Huntington’s disease, a genetic disorder marked by notable cerebral and peripheral inflammation. We summarize ongoing and completed clinical trials that have involved pharmacological approaches to inhibit various components of the immune system and their pre-clinical correlates. We then discuss new putative treatment strategies using more targeted immunotherapies such as vaccination and intrabodies and how these may offer new hope in the treatment of Huntington’s disease as well as other neurodegenerative diseases.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Soulet D, Cicchetti F. The role of immunity in Huntington’s disease. Mol Psychiatry. 2011;16:889–902.

    CAS  Google Scholar 

  2. 2.

    Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, et al. Huntington disease. Nat Rev Dis Prim. 2015;1:10155.

    Google Scholar 

  3. 3.

    Crotti A, Glass CK. The choreography of neuroinflammation in Huntington’s disease. Trends Immunol. 2015;36:364–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Politis M, Pavese N, Tai YF, Kiferle L, Mason SL, Brooks DJ, et al. Microglial activation in regions related to cognitive function predicts disease onset in Huntington’s disease: a multimodal imaging study. Hum Brain Mapp. 2011;32:258–70.

    Google Scholar 

  5. 5.

    Björkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med. 2008;205:1869–77.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Dalrymple A, Wild EJ, Joubert R, Sathasivam K, Björkqvist M, Petersén A, et al. Proteomic profiling of plasma in Huntington’s disease reveals neuroinflammatory activation and biomarker candidates. J Proteome Res. 2007;6:2833–40.

    CAS  Google Scholar 

  7. 7.

    Wild E, Magnusson A, Lahiri N, Krus U, Orth M, Tabrizi SJ, et al. Abnormal peripheral chemokine profile in Huntington’s disease. PLoS Curr. 2011;3:RRN1231 

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, et al. Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain 2007;130:1759–66.

    Google Scholar 

  9. 9.

    Kwan W, Träger U, Davalos D, Chou A, Bouchard J, Andre R, et al. Mutant huntingtin impairs immune cell migration in Huntington disease. J Clin Invest. 2012;122:4737–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    van der Burg JMM, Björkqvist M, Brundin P. Beyond the brain: widespread pathology in Huntington’s disease. Lancet Neurol. 2009;8:765–74.

    Google Scholar 

  11. 11.

    Träger U, Andre R, Lahiri N, Magnusson-Lind A, Weiss A, Grueninger S, et al. HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFκB pathway dysregulation. Brain. 2014;137:819–33.

    Google Scholar 

  12. 12.

    Ramsingh AI, Manley K, Rong Y, Reilly A, Messer A. Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington′s disease. Hum Mol Genet. 2015;24:6186–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kwan W, Magnusson A, Chou A, Adame A, Carson MJ, Kohsaka S, et al. Bone marrow transplantation confers modest benefits in Mouse models of Huntington’s disease. J Neurosci. 2012;32:133–42.

    CAS  Google Scholar 

  14. 14.

    Huntington Study Group TREND-HD Investigators. Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study. Arch Neurol. 2008;65:1582–9.

    Google Scholar 

  15. 15.

    Hickey MA, Chesselet M-F. Apoptosis in Huntington’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:255–65.

    CAS  Google Scholar 

  16. 16.

    Singhrao SK, Neal JW, Morgan BP, Gasque P. Increased complement biosynthesis by microglia and complement activation on neurons in Huntington’s disease. Exp Neurol. 1999;159:362–76.

    CAS  Google Scholar 

  17. 17.

    Panov AV, Gutekunst C-A, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci. 2002;5:731–6.

    CAS  Google Scholar 

  18. 18.

    Jump DB. The biochemistry of n-3 polyunsaturated fatty acids. J Biol Chem. 2002;277:8755–8.

    CAS  Google Scholar 

  19. 19.

    Murck H, Manku M. Ethyl-EPA in Huntington disease: potentially relevant mechanism of action. Brain Res Bull. 2007;72:159–64.

    CAS  Google Scholar 

  20. 20.

    Moon D-O, Kim K-C, Jin C-Y, Han M-H, Park C, Lee K-J, et al. Inhibitory effects of eicosapentaenoic acid on lipopolysaccharide-induced activation in BV2 microglia. Int Immunopharmacol. 2007;7:222–9.

    CAS  Google Scholar 

  21. 21.

    Minogue AM, Lynch AM, Loane DJ, Herron CE, Lynch MA. Modulation of amyloid-beta-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid. J Neurochem. 2007;103:914–26.

    CAS  Google Scholar 

  22. 22.

    Lo CJ, Chiu KC, Fu M, Lo R, Helton S. Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity. J Surg Res. 1999;82:216–21.

    CAS  Google Scholar 

  23. 23.

    Zhao Y, Joshi-Barve S, Barve S, Chen LH. Eicosapentaenoic acid prevents LPS-induced TNF-alpha expression by preventing NF-kappaB activation. J Am Coll Nutr. 2004;23:71–8.

    CAS  Google Scholar 

  24. 24.

    Clifford JJ, Drago J, Natoli AL, Wong JYF, Kinsella A, Waddington JL, et al. Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease. Neuroscience. 2002;109:81–8.

    CAS  Google Scholar 

  25. 25.

    Van Raamsdonk JM, Pearson J, Rogers DA, Lu G, Barakauskas VE, Barr AM, et al. Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease. Exp Neurol. 2005;196:266–72.

    Google Scholar 

  26. 26.

    Vaddadi KS, Soosai E, Chiu E, Dingjan P. A randomised, placebo-controlled, double blind study of treatment of Huntington’s disease with unsaturated fatty acids. Neuroreport. 2002;13:29–33.

    CAS  Google Scholar 

  27. 27.

    Puri BK, Bydder GM, Counsell SJ, Corridan BJ, Richardson AJ, Hajnal JV, et al. MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment. Neuroreport. 2002;13:123–6.

    Google Scholar 

  28. 28.

    Puri BK, Bydder GM, Manku MS, Clarke A, Waldman AD, Beckmann CF. Reduction in cerebral atrophy associated with ethyl-eicosapentaenoic acid treatment in patients with Huntington’s disease. J Int Med Res. 2008;36:896–905.

    CAS  Google Scholar 

  29. 29.

    M.E. Cudkowicz, M. McDermott, R. Doolan, F. Marshall, K. Kieburtz, HSG. ​A phase 2 trial of minocycline in Huntington’s disease. Mov Disord. 2009;24:S1–653.

  30. 30.

    Huntington Study Group DOMINO Investigators. A futility study of minocycline in Huntington’s disease. Mov Disord. 2010;25:2219–24.

    Google Scholar 

  31. 31.

    Huntington Study Group. Minocycline safety and tolerability in Huntington disease. Neurology. 2004;63:547–9.

    Google Scholar 

  32. 32.

    Thomas M, Ashizawa T, Jankovic J. Minocycline in Huntington’s disease: a pilot study. Mov Disord. 2004;19:692–5.

    Google Scholar 

  33. 33.

    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med. 2000;6:797–801.

    CAS  Google Scholar 

  34. 34.

    Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington’s disease. Proc Natl Acad Sci USA. 2003;100:10483–7.

    CAS  Google Scholar 

  35. 35.

    Stack EC, Smith KM, Ryu H, Cormier K, Chen M, Hagerty SW, et al. Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington’s disease mice. Biochim Biophys Acta. 2006;1762:373–80.

    CAS  Google Scholar 

  36. 36.

    Zhu S, Stavrovskaya IG, Drozda M, Kim BYS, Ona V, Li M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature. 2002;417:74–8.

    CAS  Google Scholar 

  37. 37.

    Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci. 2002;22:1763–71.

    CAS  Google Scholar 

  38. 38.

    Diguet E, Rouland R, Tison F. Minocycline is not beneficial in a phenotypic mouse model of Huntington’s disease. Ann Neurol. 2003;54:841–2.

    Google Scholar 

  39. 39.

    Diguet E, Fernagut P-O, Wei X, Du Y, Rouland R, Gross C, et al. Deleterious effects of minocycline in animal models of Parkinson’s disease and Huntington’s disease. Eur J Neurosci. 2004;19:3266–76.

    Google Scholar 

  40. 40.

    Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PAS, et al. Minocycline and doxycycline are not beneficial in a model of Huntington’s disease. Ann Neurol. 2003;54:186–96.

    CAS  Google Scholar 

  41. 41.

    Bantubungi K, Jacquard C, Greco A, Pintor A, Chtarto A, Tai K, et al. Minocycline in phenotypic models of Huntington’s disease. Neurobiol Dis. 2005;18:206–17.

    CAS  Google Scholar 

  42. 42.

    Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, et al. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington’s disease models. Hum Mol Genet. 2006;15:2743–51.

    CAS  Google Scholar 

  43. 43.

    Santangelo C, Varì R, Scazzocchio B, Di Benedetto R, Filesi C, Masella R. Polyphenols, intracellular signalling and inflammation. Ann Ist Super Sanita. 2007;43:394–405.

    CAS  Google Scholar 

  44. 44.

    Relja B, Töttel E, Breig L, Henrich D, Schneider H, Marzi I, et al. Plant polyphenols attenuate hepatic injury after hemorrhage/resuscitation by inhibition of apoptosis, oxidative stress, and inflammation via NF-kappaB in rats. Eur J Nutr. 2012;51:311–21.

    CAS  Google Scholar 

  45. 45.

    Kang KS, Wen Y, Yamabe N, Fukui M, Bishop SC, Zhu BT. Dual beneficial effects of (-)-epigallocatechin-3-gallate on levodopa methylation and hippocampal neurodegeneration: in vitro and in vivo studies. PLoS ONE. 2010;5:e11951.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Xu Z, Chen S, Li X, Luo G, Li L, Le W. Neuroprotective effects of (-)-epigallocatechin-3-gallate in a transgenic mouse model of amyotrophic lateral sclerosis. Neurochem Res. 2006;31:1263–9.

    CAS  Google Scholar 

  47. 47.

    Li R, Huang Y-G, Fang D, Le W-D. (-)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury. J Neurosci Res. 2004;78:723–31.

    CAS  Google Scholar 

  48. 48.

    Cheng-Chung Wei J, Huang H-C, Chen W-J, Huang C-N, Peng C-H, Lin C-L. Epigallocatechin gallate attenuates amyloid β-induced inflammation and neurotoxicity in EOC 13.31 microglia. Eur J Pharmacol. 2016;770:16–24.

    CAS  Google Scholar 

  49. 49.

    Boadas-Vaello P, Verdú E. Epigallocatechin-3-gallate treatment to promote neuroprotection and functional recovery after nervous system injury. Neural Regen Res. 2015;10:1390–2.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Ichikawa D, Matsui A, Imai M, Sonoda Y, Kasahara T. Effect of various catechins on the IL-12p40 production by murine peritoneal macrophages and a macrophage cell line, J774.1. Biol Pharm Bull. 2004;27:1353–8.

    CAS  Google Scholar 

  51. 51.

    Kundu JK, Na H-K, Chun K-S, Kim Y-K, Lee SJ, Lee SS, et al. Inhibition of phorbol ester-induced COX-2 expression by epigallocatechin gallate in mouse skin and cultured human mammary epithelial cells. J Nutr. 2003;133:3805S–3810S.

    CAS  Google Scholar 

  52. 52.

    Gratuze M, Noël A, Julien C, Cisbani G, Milot-Rousseau P, Morin F, et al. Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington’s disease. Hum Mol Genet. 2015;24:86–99.

    CAS  Google Scholar 

  53. 53.

    Vuono R, Winder-Rhodes S, de Silva R, Cisbani G, Drouin-Ouellet J, REGISTRY Investigators of the European Huntington’s Disease Network. et al. The role of tau in the pathological process and clinical expression of Huntington’s disease. Brain. 2015;138:1907–18.

    Google Scholar 

  54. 54.

    Cisbani G, Maxan A, Kordower JH, Planel E, Freeman TB, Cicchetti F. Presence of tau pathology within fetal neural allografts in patients with Huntington’s and Parkinson’s disease. Brain. 2017;140:2982–92.

    Google Scholar 

  55. 55.

    Wobst HJ, Sharma A, Diamond MI, Wanker EE, Bieschke J. The green tea polyphenol (−)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett. 2015;589:77–83.

    CAS  Google Scholar 

  56. 56.

    López-Sendón Moreno JL, García Caldentey J, Trigo Cubillo P, Ruiz Romero C, García Ribas G, Alonso Arias MAA, et al. A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease. J Neurol. 2016;263:1390–400.

    Google Scholar 

  57. 57.

    Valdeolivas S, Satta V, Pertwee RG, Fernández-Ruiz J, Sagredo O. Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: role of CB1 and CB2 receptors. ACS Chem Neurosci. 2012;3:400–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM. Biased type 1 cannabinoid receptor signaling influences neuronal viability in a cell culture model of Huntington disease. Mol Pharmacol. 2016;89:364–75.

    CAS  Google Scholar 

  59. 59.

    Blázquez C, Chiarlone A, Bellocchio L, Resel E, Pruunsild P, García-Rincón D, et al. The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death Differ. 2015;22:1618–29.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science. 2001;293:493–8.

    CAS  PubMed  Google Scholar 

  61. 61.

    Dowie MJ, Howard ML, Nicholson LFB, Faull RLM, Hannan AJ, Glass M. Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington’s disease transgenic mice. Neuroscience. 2010;170:324–36.

    CAS  Google Scholar 

  62. 62.

    Navarro G, Morales P, Rodríguez-Cueto C, Fernández-Ruiz J, Jagerovic N, Franco R. Targeting cannabinoid CB2 receptors in the central nervous system. medicinal chemistry approaches with focus on neurodegenerative disorders. Front Neurosci. 2016;10:406 

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Sagredo O, González S, Aroyo I, Pazos MR, Benito C, Lastres-Becker I, et al. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington’s disease. Glia. 2009;57:1154–67.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Dowie MJ, Grimsey NL, Hoffman T, Faull RLM, Glass M. Cannabinoid receptor CB2 is expressed on vascular cells, but not astroglial cells in the post-mortem human Huntington’s disease brain. J Chem Neuroanat. 2014;59–60:62–71.

    Google Scholar 

  65. 65.

    Bouchard J, Truong J, Bouchard K, Dunkelberger D, Desrayaud S, Moussaoui S, et al. Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington’s disease. J Neurosci. 2012;32:18259–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet. 2003;35:76–83.

    CAS  Google Scholar 

  67. 67.

    Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366:1000–9.

    CAS  Google Scholar 

  68. 68.

    Brück W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci. 2011;306:173–9.

    Google Scholar 

  69. 69.

    Thöne J, Gold R. Laquinimod: a promising oral medication for the treatment of relapsing-remitting multiple sclerosis. Expert Opin Drug Metab Toxicol. 2011;7:365–70.

    Google Scholar 

  70. 70.

    Garcia-Miralles M, Hong X, Tan LJ, Caron NS, Huang Y, To XV, et al. Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease. Sci Rep. 2016;6:31652 

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Ellrichmann G, Blusch A, Fatoba O, Brunner J, Hayardeny L, Hayden M, et al. Laquinimod treatment in the R6/2 mouse model. Sci Rep. 2017;7:4947.

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Dobson L, Träger U, Farmer R, Hayardeny L, Loupe P, Hayden MR, et al. Laquinimod dampens hyperactive cytokine production in Huntington’s disease patient myeloid cells. J Neurochem. 2016;137:782–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Okuno T, Nakatsuji Y, Moriya M, Takamatsu H, Nojima S, Takegahara N, et al. Roles of Sema4D-plexin-B1 interactions in the central nervous system for pathogenesis of experimental autoimmune encephalomyelitis. J Immunol. 2010;184:1499–506.

    CAS  Google Scholar 

  74. 74.

    Hodges A, Strand AD, Aragaki AK, Kuhn A, Sengstag T, Hughes G, et al. Regional and cellular gene expression changes in human Huntington’s disease brain. Hum Mol Genet. 2006;15:965–77.

    CAS  Google Scholar 

  75. 75.

    Smith ES, Jonason A, Reilly C, Veeraraghavan J, Fisher T, Doherty M, et al. SEMA4D compromises blood–brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol Dis. 2015;73:254–68.

    CAS  Google Scholar 

  76. 76.

    Southwell AL, Franciosi S, Villanueva EB, Xie Y, Winter LA, Veeraraghavan J, et al. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2015;76:46–56.

    CAS  Google Scholar 

  77. 77.

    Granja AG, Carrillo-Salinas F, Pagani A, Gómez-Cañas M, Negri R, Navarrete C, et al. A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis. J NeuroImmune Pharmacol. 2012;7:1002–16.

    Google Scholar 

  78. 78.

    Carrillo-Salinas FJ, Navarrete C, Mecha M, Feliú A, Collado JA, Cantarero I, et al. A cannabigerol derivative suppresses immune responses and protects mice from experimental autoimmune encephalomyelitis. PLoS ONE. 2014;9:e94733.

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Dickey AS, Pineda VV, Tsunemi T, Liu PP, Miranda HC, Gilmore-Hall SK, et al. PPAR-δ is repressed in Huntington’s disease, is required for normal neuronal function and can be targeted therapeutically. Nat Med. 2016;22:37–45.

    CAS  Google Scholar 

  80. 80.

    Corona JC, Duchen MR. PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease. Free Radic Biol Med. 2016;100:153–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Díaz-Alonso J, Paraíso-Luna J, Navarrete C, Del Río C, Cantarero I, Palomares B, et al. VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington’s disease. Sci Rep. 2016;6:29789.

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WEF, et al. Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med. 1999;189:865–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Kruse N, Cetin S, Chan A, Gold R, Lühder F. Differential expression of BDNF mRNA splice variants in mouse brain and immune cells. J Neuroimmunol. 2007;182:13–21.

    CAS  Google Scholar 

  84. 84.

    Xu D, Lian D, Wu J, Liu Y, Zhu M, Sun J, et al. Brain-derived neurotrophic factor reduces inflammation and hippocampal apoptosis in experimental Streptococcus pneumoniae meningitis. J Neuroinflamm. 2017;14:156 

    Google Scholar 

  85. 85.

    Massa SM, Yang T, Xie Y, Shi J, Bilgen M, Joyce JN, et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest. 2010;120:1774–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Longo FM, Massa SM. Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov. 2013;12:507–25.

    Google Scholar 

  87. 87.

    Simmons DA, Belichenko NP, Yang T, Condon C, Monbureau M, Shamloo M, et al. A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington’s disease. J Neurosci. 2013;33:18712–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Alto LT, Chen X, Ruhn KA, Treviño I, Tansey MG. AAV-dominant negative tumor necrosis factor (DN-TNF) gene transfer to the striatum does not rescue medium spiny neurons in the YAC128 mouse model of Huntington’s disease. PLoS ONE. 2014;9:e96544.

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Hsiao H-Y, Chiu F-L, Chen C-M, Wu Y-R, Chen H-M, Chen Y-C, et al. Inhibition of soluble tumor necrosis factor is therapeutic in Huntington’s disease. Hum Mol Genet. 2014;23:4328–44.

    CAS  Google Scholar 

  90. 90.

    Newton R, Seybold J, Kuitert LME, Bergmann M, Barnes PJ. Repression of cyclooxygenase-2 and prostaglandin E2release by dexamethasone occurs by transcriptional and post-transcriptional mechanisms involving loss of polyadenylated mRNA. J Biol Chem. 1998;273:32312–21.

    CAS  Google Scholar 

  91. 91.

    Diamond MI, Robinson MR, Yamamoto KR. Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor. Proc Natl Acad Sci. 2000;97:657–61.

    CAS  Google Scholar 

  92. 92.

    Maheshwari M, Bhutani S, Das A, Mukherjee R, Sharma A, Kino Y, et al. Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington’s disease. Hum Mol Genet. 2014;23:2737–51.

    CAS  Google Scholar 

  93. 93.

    Chafekar SM, Duennwald ML. Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin. PLoS ONE. 2012;7:e37929.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Moseley PL. Heat shock proteins and the inflammatory response. Ann N Y Acad Sci. 1998;856:206–13.

    CAS  Google Scholar 

  95. 95.

    Nuti A, Maremmani C, Ceravolo R, Pavese N, Bonuccelli U, Muratorio A. [Dexamethasone therapy in Huntington chorea: preliminary results]. Riv Neurol. 1991;61:225–7.

    CAS  Google Scholar 

  96. 96.

    Ellison SM, Trabalza A, Tisato V, Pazarentzos E, Lee S, Papadaki V, et al. Dose-dependent neuroprotection of VEGF165 in Huntington’s disease striatum. Mol Ther. 2013;21:1862–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Fossale E, Wheeler VC, Vrbanac V, Lebel L-A, Teed A, Mysore JS, et al. Identification of a presymptomatic molecular phenotype in Hdh CAG knock-in mice. Hum Mol Genet. 2002;11:2233–41.

    CAS  Google Scholar 

  98. 98.

    Carnemolla A, Fossale E, Agostoni E, Michelazzi S, Calligaris R, De Maso L, et al. Rrs1 is involved in endoplasmic reticulum stress response in Huntington disease. J Biol Chem. 2009;284:18167–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Egea J, Buendia I, Parada E, Navarro E, León R, Lopez MG. Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection. Biochem Pharmacol. 2015;97:463–72.

    CAS  Google Scholar 

  100. 100.

    Ryu JK, Kim SU, McLarnon JG. Blockade of quinolinic acid-induced neurotoxicity by pyruvate is associated with inhibition of glial activation in a model of Huntington’s disease. Exp Neurol. 2004;187:150–9.

    CAS  Google Scholar 

  101. 101.

    Ryu JK, Choi HB, McLarnon JG. Combined minocycline plus pyruvate treatment enhances effects of each agent to inhibit inflammation, oxidative damage, and neuronal loss in an excitotoxic animal model of Huntington’s disease. Neuroscience. 2006;141:1835–48.

    CAS  Google Scholar 

  102. 102.

    Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci. 2000;20:4389–97.

    CAS  Google Scholar 

  103. 103.

    Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003;53:267–70.

    CAS  Google Scholar 

  104. 104.

    Miller TW, Shirley TL, Wolfgang WJ, Kang X, Messer A. DNA vaccination against mutant huntingtin ameliorates the HDR6/2 diabetic phenotype. Mol Ther. 2003;7:572–9.

    CAS  Google Scholar 

  105. 105.

    Marschall ALJ, Dübel S. Antibodies inside of a cell can change its outside: can intrabodies provide a new therapeutic paradigm? Comput Struct Biotechnol J. 2016;14:304–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Khoshnan A, Ko J, Patterson PH. Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc Natl Acad Sci USA. 2002;99:1002–7.

    CAS  Google Scholar 

  107. 107.

    Lecerf J-M, Shirley TL, Zhu Q, Kazantsev A, Amersdorfer P, Housman DE, et al. Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington’s disease. Proc Natl Acad Sci USA. 2001;98:4764–9.

    CAS  Google Scholar 

  108. 108.

    Snyder-Keller A, McLear JA, Hathorn T, Messer A. Early or late-stage anti-N-terminal Huntingtin intrabody gene therapy reduces pathological features in B6.HDR6/1 mice. J Neuropathol Exp Neurol. 2010;69:1078–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Southwell AL, Ko J, Patterson PH. Intrabody gene therapy ameliorates motor, cognitive and neuropathological symptoms in multiple mouse models of Huntington’s disease. J Neurosci. 2009;29:13589.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Zha J, Liu X-M, Zhu J, Liu S-Y, Lu S, Xu P-X, et al. A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses. Sci Rep. 2016;6:36631.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Messer A, Joshi SN. Intrabodies as neuroprotective therapeutics. Neurotherapeutics.2013;10:447–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Butler DC, Messer A. Bifunctional anti-Huntingtin proteasome-directed intrabodies mediate efficient degradation of mutant Huntingtin exon 1 protein fragments. PLoS ONE. 2011;6:e29199.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Carroll JB, Bates GP, Steffan J, Saft C, Tabrizi SJ. Treating the whole body in Huntington’s disease. Lancet Neurol. 2015;14:1135–42.

    Google Scholar 

  114. 114.

    Jeon I, Cicchetti F, Cisbani G, Lee S, Li E, Bae J, et al. Human-to-mouse prion-like propagation of mutant Huntingtin protein. Acta Neuropathol (Berl). 2016;132:577–92.

    CAS  Google Scholar 

  115. 115.

    Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R, et al. Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci. 1999;19:2522–34.

    CAS  Google Scholar 

  116. 116.

    Liu X, Valentine SJ, Plasencia MD, Trimpin S, Naylor S, Clemmer DE. Mapping the human plasma proteome by SCX-LC-IMS-MS. J Am Soc Mass Spectrom. 2007;18:1249–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JRC, et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J Clin Invest. 2015;125:1979–86.

    PubMed  PubMed Central  Google Scholar 

  118. 118.

    Bartl S, Southwell AL, Parth M, Salhat N, Burkert M, Siddu A, et al. Antibody-based targeting of mutant Huntingtin for the treatment of Huntington’s disease. Abstract, 12th Annual Huntington's Disease Therapeutics Conference, CHDI Foundation April 2017.

  119. 119.

    OW Smrzka, Southwell AL, Bartl S, Parth M, Burkert M, Villanueva EB, et al. Passive treatment with huntingtin (HTT)-specific mAb’s lowers HTT levels and improves motor performance in YAC128 mice. Abstract, 11th Annual Huntington's Disease Therapeutics Conference, CHDI Foundation February 2017.

  120. 120.

    Main BS, Minter MR. Microbial immuno-communication in neurodegenerative diseases. Front Neurosci. 2017;11:151

    PubMed  PubMed Central  Google Scholar 

  121. 121.

    Rosas HD, Doros G, Bhasin S, Thomas B, Gevorkian S, Malarick K, et al. A systems-level “misunderstanding”: the plasma metabolome in Huntington’s disease. Ann Clin Transl Neurol. 2015;2:756–68.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

FC is a recipient of a Researcher Chair from the Fonds de Recherche du Québec en Santé (FRQS) 35059 providing salary support and operating funds, and receives funding from the Canadian Institutes of Health Research (CIHR) MOP326050 to conduct her HD-related research. FL holds a Joseph Demers scholarship award from Université Laval and HLD a Desjardins scholarship from the Fondation du CHU de Québec. We would like to thank Mr. Gilles Chabot for artwork.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Francesca Cicchetti.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Denis, H., Lauruol, F. & Cicchetti, F. Are immunotherapies for Huntington’s disease a realistic option?. Mol Psychiatry 24, 364–377 (2019). https://doi.org/10.1038/s41380-018-0021-9

Download citation

Further reading

Search

Quick links