Nonhuman Primate Models of Huntington’s Disease and Their Application in Translational Research

  • Romina Aron BadinEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1780)


Huntington’s disease (HD) is a monogenic, autosomal dominant inherited fatal disease that affects 1 in 10,000 people worldwide. Given its unique genetic characteristics, HD would appear as one of the most straightforward neurodegenerative diseases to replicate in animal models. Indeed, mutations in the HTT gene have been used to generate a variety of animal models that display differential pathologies and have significantly increased our understanding of the pathological mechanisms of HD. However, decades of efforts have also shown the complexity of recapitulating the human condition in other species. Here we describe the three different types of models that have been generated in nonhuman primate species, stating their advantages and limitations and attempt to give a critical perspective of their translational value to test the efficacy of novel therapeutic strategies. Obtaining construct, phenotypic, and predictive validity has proven to be challenging in most animal models of human diseases. In HD in particular, it is hard to assess the predictive validity of a new therapeutic strategy when no effective “benchmark” treatment is available in the clinic. In this light, only phenotypic/face validity and construct validity are discussed.

Key words

Huntington’s disease Animal models Non-human primates Preclinical efficacy Translational research 



The authors acknowledge that the genetic model of HD in primates was jointly developed with Dr. Nicole Déglon and Dr. Marta Ruiz.


  1. 1.
    Duyao M, Ambrose C, Myers R et al (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–392PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983CrossRefGoogle Scholar
  3. 3.
    Shao J, Welch WJ, Diprospero NA, Diamond MI (2008) Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation. Mol Cell Biol 28:5196–5208PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Tobin AJ, Signer ER (2000) Huntington’s disease: the challenge for cell biologists. Trends Cell Biol 10:531–536PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 6:919–930PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Vonsattel JP, Myers RH, Stevens TJ et al (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Ferrante RJ, Kowall NW, Beal MF et al (1985) Selective sparing of a class of striatal neurons in Huntington’s disease. Science 230(4725):561–563PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Ferrante RJ, Beal MF, Kowall NW et al (1987) Sparing of acetylcholinesterase-containing striatal neurons in Huntington’s disease. Brain Res 411:162–166PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kowall NW, Quigley BJ Jr, Krause JE et al (1993) Substance P and substance P receptor histochemistry in human neurodegenerative diseases. Regul Pept 46:174–185PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Cicchetti F, Prensa L, Wu Y, Parent A (2000) Chemical anatomy of striatal interneurons in normal individuals and in patients with Huntington’s disease. Brain Res Rev 34(1–2):80–101PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Walker FO (2007) Huntington’s disease. Semin Neurol 27(2):143–150PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Lawrence AD, Sahakian BJ, Hodges JR et al (1996) Executive and mnemonic functions in early Huntington’s disease. Brain 119:1633–1645PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Cummings JL (1995) Behavioral and psychiatric symptoms associated with Huntington’s disease. Adv Neurol 65:179–186PubMedPubMedCentralGoogle Scholar
  14. 14.
    Duff K, Paulsen JS, Beglinger LJ et al (2007) Psychiatric symptoms in Huntington’s disease before diagnosis: the predict-HD study. Biol Psychiatry 62:1341–1346PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Marshall J, White K, Weaver M et al (2007) Specific psychiatric manifestations among preclinical Huntington disease mutation carriers. Arch Neurol 64:116–121PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Huntington G (2003) On chorea. George Huntington, M.D. J Neuropsychiatry Clin Neurosci 15:109–112PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Young AB, Shoulson I, Penney JB et al (1986) Huntington’s disease in Venezuela: neurologic features and functional decline. Neurology 36:244–249PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Ramaswamy S, McBride JL, Kordower JH (2007) Animal models of Huntington’s disease. ILAR J 48:356–373PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Pouladi MA, Morton AJ, Hayden MR (2013) Choosing an animal model for the study of Huntington’s disease. Nat Rev Neurosci 14:708–721CrossRefGoogle Scholar
  20. 20.
    Hantraye P, Riche D, Maziere M, Isacson O (1990) A primate model of Huntington’s disease: behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. Exp Neurol 108:91–104PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Kanazawa I, Tanaka Y, Cho F (1986) ‘Choreic’ movement induced by unilateral kainate lesion of the striatum and L-DOPA administration in monkey. Neurosci Lett 71:241–246PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kanazawa I, Sasaki H, Muramoto O et al (1985) Studies on neurotransmitter markers and striatal neuronal cell density in Huntington’s disease and dentatorubropallidoluysian atrophy. J Neurol Sci 70:151–165PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ferrante RJ, Kowall NW, Cipolloni PB et al (1993) Excitotoxin lesions in primates as a model for Huntington’s disease: histopathologic and neurochemical characterization. Exp Neurol 119:46–71PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Burns LH, Pakzaban P, Deacon TW et al (1995) Selective putaminal excitotoxic lesions in non-human primates model the movement disorder of Huntington disease. Neuroscience 64:1007–1017PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Roitberg BZ, Emborg ME, Sramek JG et al (2002) Behavioral and morphological comparison of two nonhuman primate models of Huntington’s disease. Neurosurgery 50:137–145. discussion 145–146PubMedPubMedCentralGoogle Scholar
  26. 26.
    DiFiglia M (1990) Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends Neurosci 13:286–289PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Schumacher JM, Hantraye P, Brownell AL et al (1992) A primate model of Huntington’s disease: functional neural transplantation and CT-guided stereotactic procedures. Cell Transplant 1:313–322PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Kendall AL, David F, Rayment G et al (2000) The influence of excitotoxic basal ganglia lesions on motor performance in the common marmoset. Brain 123:1442–1458CrossRefPubMedGoogle Scholar
  29. 29.
    Brownell AL, Hantraye P, Wullner U et al (1994) PET- and MRI-based assessment of glucose utilization, dopamine receptor binding, and hemodynamic changes after lesions to the caudate-putamen in primates. Exp Neurol 125:41–51PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Schwarcz R, Tamminga CA, Kurlan R, Shoulson I (1988) Cerebrospinal fluid levels of quinolinic acid in Huntington’s disease and schizophrenia. Ann Neurol 24:580–582. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Campbell BM, Charych E, Lee AW, Moller T (2014) Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci 8:12. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Beal MF, Kowall NW, Ellison DW et al (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321(6066):168–171PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gardian G, Vecsei L (2004) Huntington’s disease: pathomechanism and therapeutic perspectives. J Neural Transm (Vienna) 111:1485–1494CrossRefGoogle Scholar
  34. 34.
    Brouillet E, Conde F, Beal MF, Hantraye P (1999) Replicating Huntington’s disease phenotype in experimental animals. Prog Neurobiol 59:427–468PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Ludolph AC, He F, Spencer PS et al (1991) 3-Nitropropionic acid-exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci 18:492–498CrossRefPubMedGoogle Scholar
  36. 36.
    Palfi S, Ferrante RJ, Brouillet E et al (1996) Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington’s disease. J Neurosci 16:3019PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Palfi S, Leventhal L, Goetz CG et al (2000) Delayed onset of progressive dystonia following subacute 3-nitropropionic acid treatment in Cebus apella monkeys. Mov Disord 15:524–530PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Brouillet E, Hantraye P (1995) Effects of chronic MPTP and 3-nitropropionic acid in nonhuman primates. Curr Opin Neurol 8:469–473PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Brouillet E, Hantraye P, Ferrante RJ et al (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc Natl Acad Sci U S A 92:7105–7109PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Beal MF, Brouillet E, Jenkins BG et al (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 13:4181–4192PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Dautry C, Conde F, Brouillet E et al (1999) Serial 1H-NMR spectroscopy study of metabolic impairment in primates chronically treated with the succinate dehydrogenase inhibitor 3-nitropropionic acid. Neurobiol Dis 6:259–268PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Dautry C, Vaufrey F, Brouillet E et al (2000) Early N-acetylaspartate depletion is a marker of neuronal dysfunction in rats and primates chronically treated with the mitochondrial toxin 3-nitropropionic acid. J Cereb Blood Flow Metab 20:789–799PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Yang SH, Cheng PH, Banta H et al (2008) Towards a transgenic model of Huntington’s disease in a non-human primate. Nature 453:921–924PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chan AW, Xu Y, Jiang J et al (2014) A two years longitudinal study of a transgenic Huntington disease monkey. BMC Neurosci 15:36. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Chan AW, Jiang J, Chen Y et al (2015) Progressive cognitive deficit, motor impairment and striatal pathology in a transgenic Huntington disease monkey model from infancy to adulthood. PLoS One 10(5):e0122335PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Storey E, Cipolloni PB, Ferrrante RJ et al (1994) Movement disorder following excitotoxin lesions in primates. Neuroreport 5:1259–1261PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Hantraye P, Leroy-Willig A, Denys A et al (1992) Magnetic resonance imaging to monitor pathology of caudate-putamen after excitotoxin-induced neuronal loss in the nonhuman primate brain. Exp Neurol 118:18–23PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kanazawa I, Kimura M, Murata M et al (1990) choreic movements in the macaque monkey induced by kainic acid lesions of the striatum combined with l-dopapharmacological, biochemical and physiological studies on neural mechanisms. Brain 113:509–535PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Baxa M, Hruska-Plochan M, Juhas S et al (2013) A transgenic minipig model of Huntington’s disease. J Huntingtons Dis 2:47–68PubMedGoogle Scholar
  50. 50.
    Morton AJ, Howland DS (2013) Large genetic animal models of Huntington’s disease. J Huntingtons Dis 2:3–19PubMedGoogle Scholar
  51. 51.
    Reid SJ, Patassini S, Handley RR et al (2013) Further molecular characterisation of the OVT73 transgenic sheep model of Huntington’s disease identifies cortical aggregates. J Huntingtons Dis 2:279–295PubMedPubMedCentralGoogle Scholar
  52. 52.
    Jacobsen JC, Bawden CS, Rudiger SR et al (2010) An ovine transgenic Huntington’s disease model. Hum Mol Genet 19:1873–1882PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Yang D, Wang CE, Zhao B et al (2010) Expression of Huntington’s disease protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum Mol Genet 19:3983–3994PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Handley RR, Reid SJ, Patassini S et al (2016) Metabolic disruption identified in the Huntington’s disease transgenic sheep model. Sci Rep 6:20681. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Chan AW, Yang SH (2009) Generation of transgenic monkeys with human inherited genetic disease. Methods 49:78–84PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Wang CE, Tydlacka S, Orr AL et al (2008) Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington’s disease. Hum Mol Genet 17:2738–2751PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Palfi S, Brouillet E, Jarraya B et al (2007) Expression of mutated huntingtin fragment in the putamen is sufficient to produce abnormal movement in non-human primates. Mol Ther 15:1444–1451PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Aron Badin R, Callander G et al (2013) Characterization of a novel striatal-specific non-human primate model of Huntington’s disease. Movement Disorders. In: 17th International Congress of the Parkinson’s Disease and Movements Disorders, Sydney, Australia, 16–20 June 2013, p. 103, abstract 754Google Scholar
  59. 59.
    Phillips KA, Bales KL, Capitanio JP et al (2014) Why primate models matter. Am J Primatol 76:801–827PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Ventura-Antunes L, Mota B, Herculano-Houzel S (2013) Different scaling of white matter volume, cortical connectivity, and gyrification across rodent and primate brains. Front Neuroanat 7:3. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Insausti R (2013) Comparative neuroanatomical parcellation of the human and nonhuman primate temporal pole. J Comp Neurol 521:4163–4176PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Roth G, Dicke U (2005) Evolution of the brain and intelligence. Trends Cogn Sci 9:250–257PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Semendeferi K, Lu A, Schenker N, Damasio H (2002) Humans and great apes share a large frontal cortex. Nat Neurosci 5:272–276PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Seelke AM, Dooley JC, Krubitzer LA (2012) The emergence of somatotopic maps of the body in S1 in rats: the correspondence between functional and anatomical organization. PLoS One 7(2):e32322PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Hantraye P, Palfi S, Mittoux V et al (2000) Replicating Huntington disease’s phenotype in nonhuman primates. In: Emerich DF, Dean RL, Sanberg PR (eds) Central nervous system diseases: innovative animal models from lab to clinic. Humana Press, Totowa, NJ, pp 333–353CrossRefGoogle Scholar
  66. 66.
    Aron Badin R, Hantraye P (2012) Designing primate models to assess the prodromal phase of Huntington’s disease. Rev Neurol 168:802–805PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Aron Badin R, Vadori M, Cozzi E, Hantraye P (2015) Translational research for Parkinsons disease: the value of pre-clinical primate models. Eur J Pharmacol 759:118–126PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Wolfe JH (2009) Gene therapy in large animal models of human genetic diseases. ILAR J 50:107–111PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Haley PJ (2003) Species differences in the structure and function of the immune system. Toxicology 188:49–71PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Isacson O, Hantraye P, Maziere M et al (1990) Apomorphine-induced dyskinesias after excitotoxic caudate-putamen lesions and the effects of neural transplantation in non-human primates. Prog Brain Res 82:523–533PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Emerich DF, Thanos CG, Goddard M et al (2006) Extensive neuroprotection by choroid plexus transplants in excitotoxin lesioned monkeys. Neurobiol Dis 23:471–480PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Isacson O, Riche D, Hantraye P et al (1989) A primate model of Huntington’s disease: cross-species implantation of striatal precursor cells to the excitotoxically lesioned baboon caudate-putamen. Exp Brain Res 75:213–220PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Simmons JT, Pastakia B, Chase TN, Shults CW (1986) Magnetic resonance imaging in Huntington disease. AJNR Am J Neuroradiol 7:25–28PubMedPubMedCentralGoogle Scholar
  74. 74.
    Palfi S, Conde F, Riche D et al (1998) Fetal striatal allografts reverse cognitive deficits in a primate model of Huntington disease. Nat Med 4:963–966PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Simmons NE, Helm GA, Cail WS et al (1994) Magnetic resonance imaging of neuronal grafts in the primate. Exp Neurol 125:52–57PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Denys A, Leroy-Willig A, Riche D, Hantraye P (1992) MR appearance of neural grafts in a primate model of Huntington disease. Am J Roentgenol 158:215–216CrossRefGoogle Scholar
  77. 77.
    Zuccato C, Cattaneo E (2007) Role of brain-derived neurotrophic factor in Huntington’s disease. Prog Neurobiol 81:294–330PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Borrell-Pages M, Canals JM, Cordelieres FP et al (2006) Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest 116:1410–1424PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Emerich DF, Winn SR, Harper J et al (1994) Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: rescue and sprouting of degenerating cholinergic basal forebrain neurons. J Comp Neurol 349:148–164PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Kordower JH, Winn SR, Liu YT et al (1994) The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor. Proc Natl Acad Sci U S A 91:10898–10902PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Emerich DF, Winn SR, Hantraye PM et al (1997) Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 386:395–399PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Mittoux V, Joseph JM, Conde F et al (2000) Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington’s disease. Hum Gene Ther 11:1177–1187PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Bachoud-Levi AC, Deglon N, Nguyen JP et al (2000) Neuroprotective gene therapy for Huntington’s disease using a polymer encapsulated BHK cell line engineered to secrete human CNTF. Hum Gene Ther 11:1723–1729PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Bloch J, Bachoud-Levi AC, Deglon N et al (2004) Neuroprotective gene therapy for Huntington’s disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study. Hum Gene Ther 15:968–975PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Emborg ME, Hurley SA, Joers V et al (2014) Titer and product affect the distribution of gene expression after intraputaminal convection-enhanced delivery. Stereotact Funct Neurosurg 92:182–194PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Moirano J, Emborg ME (2006) Chapter 9 – Nonhuman primate models for testing gene therapy for neurodegenerative disorders A2 – Kaplitt, Michael G. In: During MJ (ed) Gene therapy of the central nervous system. Academic Press, Amsterdam, pp 109–119CrossRefGoogle Scholar
  87. 87.
    Ramaswamy S, Kordower JH (2012) Gene therapy for Huntington’s disease. Neurobiol Dis 48:243–254PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Ruozi B, Belletti D, Bondioli L et al (2012) Neurotrophic factors and neurodegenerative diseases: a delivery issue. Int Rev Neurobiol 102:207–247PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Keiser MS, Kordasiewicz HB, McBride JL (2016) Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington’s disease and spinocerebellar ataxia. Hum Mol Genet 25:R53–R64PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Godinho BM, Malhotra M, O’Driscoll CM, Cryan JF (2015) Delivering a disease-modifying treatment for Huntington’s disease. Drug Discov Today 20:50–64PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Pfister EL, Kennington L, Straubhaar J et al (2009) Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr Biol 19:774–778PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Ruiz M, Deglon N (2012) Viral-mediated overexpression of mutant huntingtin to model HD in various species. Neurobiol Dis 48:202–211PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Hadaczek P, Eberling JL, Pivirotto P et al (2010) Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol Ther 18:1458–1461PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Drouet V, Perrin V, Hassig R et al (2009) Sustained effects of nonallele-specific Huntingtin silencing. Ann Neurol 65:276–285PubMedCrossRefGoogle Scholar
  95. 95.
    Lombardi MS, Jaspers L, Spronkmans C et al (2009) A majority of Huntington’s disease patients may be treatable by individualized allele-specific RNA interference. Exp Neurol 217:312–319PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Ostergaard ME, Southwell AL, Kordasiewicz H et al (2013) Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant Huntingtin in the CNS. Nucleic Acids Res 41:9634–9650PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    McBride JL, Pitzer MR, Boudreau R et al (2011) Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol Ther 19:2152–2162PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Grondin R, Kaytor MD, Ai Y, Nelson PT et al (2012) Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 135:1197–1209PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Stiles DK, Zhang Z, Ge P et al (2012) Widespread suppression of huntingtin with convection-enhanced delivery of siRNA. Exp Neurol 233:463–471PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Grondin R, Ge P, Chen Q et al (2015) Onset time and durability of huntingtin suppression in rhesus putamen after direct infusion of antihuntingtin siRNA. Mol Ther Nucleic Acids 4:e245PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Kordasiewicz HB, Stanek LM, Wancewicz EV et al (2012) Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74:1031–1044PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Downs ME, Buch A, Sierra C et al (2015) Correction: Long-term safety of repeated blood-brain barrier opening via focused ultrasound with microbubbles in non-human primates performing a cognitive task. PLoS One 10:e0130860PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Kumar A, Kumar Singh S, Kumar V et al (2015) Huntington’s disease: an update of therapeutic strategies. Gene 556:91–97PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ripaud L, Chumakova V, Antonin M et al (2014) Overexpression of Q-rich prion-like proteins suppresses polyQ cytotoxicity and alters the polyQ interactome. Proc Natl Acad Sci U S A 111:18219–18224PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Faideau M, Kim J, Cormier K et al (2010) In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington’s disease subjects. Hum Mol Genet 19:3053–3067PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Crotti A, Glass CK (2015) The choreography of neuroinflammation in Huntington’s disease. Trends Immunol 36:364–373PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Benraiss A, Wang S, Herrlinger S et al (2016) Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat Commun 7:11758PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Escartin C, Bonvento G (2008) Targeted activation of astrocytes: a potential neuroprotective strategy. Mol Neurobiol 38:231–241PubMedPubMedCentralCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Commissariat à l’Energie Atomique (CEA)Molecular Imaging Research Center (MIRCen)Fontenay-aux-RosesFrance
  2. 2.Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases LaboratoryFontenay-aux-RosesFrance

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