Advertisement

Gene Therapy for Huntington’s Disease

  • Angela Wu
  • Dahna M. Fong
  • Deborah YoungEmail author
Protocol
Part of the Neuromethods book series (NM, volume 98)

Abstract

Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease characterized by loss of motor control, cognitive decline, and psychiatric manifestations. The underlying genetic cause of HD is a mutation in the huntingtin gene resulting in an expanded polyglutamine tract in huntingtin protein that confers a toxic gain of function. Abnormal intranuclear protein inclusions and the progressive degeneration of medium spiny neurons in the striatum as well as other brain areas at later stages are key neuropathological features of the disease. Gene therapy is an attractive therapeutic option for HD. Therapeutic strategies have primarily centered on neuroprotective and/or neuroregenerative approaches to prevent or ameliorate the extent of striatal neuron loss through the overexpression of neurotrophic factors which boost the resilience of neurons to the toxic effects of mutant huntingtin. More recently, attention has turned to gene silencing or intrabody approaches, powerful approaches that aim to mitigate the pathogenic effects of mutant huntingtin. Promising results have been shown in the evaluation of several of these strategies in rodent and non-human primate models of HD, and gene delivery technology has advanced to the stage where opportunities for long-term therapeutic intervention can be realized. In this chapter, we review the main gene therapy strategies for HD followed by a description of the methods used in our laboratory for the packaging of adeno-associated viral (AAV) vectors for therapeutic gene delivery, methods for AAV vector delivery into the rodent brain, and behavioral tests used for the assessment of functional deficits/recovery in rat models of HD.

Key words

Gene therapy Huntington’s disease Animal models Adeno-associated viral vectors RNA interference Neurotrophic factors Intrabodies 

References

  1. 1.
    MacDonald ME, Ambrose CM, Duyao MP et al (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72(6):971–983CrossRefGoogle Scholar
  2. 2.
    DiFiglia M, Sapp E, Chase KO et al (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277(5334):1990–1993PubMedCrossRefGoogle Scholar
  3. 3.
    Reiner A, Albin RL, Anderson KD et al (1988) Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci U S A 85(15):5733–5737PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Vonsattel J, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57(5):369–384PubMedCrossRefGoogle Scholar
  5. 5.
    Imarisio S, Carmichael J, Korolchuk V et al (2008) Huntington’s disease: from pathology and genetics to potential therapies. Biochem J 412:191–209PubMedCrossRefGoogle Scholar
  6. 6.
    Thompson J, Snowden J, Craufurd D et al (2002) Behavior in Huntington’s disease: dissociating cognition-based and mood-based changes. J Neuropsychiatry Clin Neurosci 14(1):37–43PubMedGoogle Scholar
  7. 7.
    Bombard Y, Penziner E, Decolongon J et al (2007) Managing genetic discrimination: strategies used by individuals found to have the Huntington disease mutation. Clin Genet 71(3):220–231PubMedCrossRefGoogle Scholar
  8. 8.
    Jacobsen JC, Bawden CS, Rudiger SR et al (2010) An ovine transgenic Huntington’s disease model. Hum Mol Genet 19(10):1873–1882PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Heng MY, Detloff PJ, Albin RL (2008) Rodent genetic models of Huntington disease. Neurobiol Dis 32(1):1–9PubMedCrossRefGoogle Scholar
  10. 10.
    Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237(4819):1154–1162PubMedCrossRefGoogle Scholar
  12. 12.
    Emerich DF, Hammang JP, Baetge EE et al (1994) Implantation of polymer-encapsulated human nerve growth factor-secreting fibroblasts attenuates the behavioral and neuropathological consequences of quinolinic acid injections into rodent striatum. Exp Neurol 130(1):141–150PubMedCrossRefGoogle Scholar
  13. 13.
    Kordower JH, Chen EY, Winkler C et al (1998) Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington’s disease. J Comp Neurol 387(1):96–113CrossRefGoogle Scholar
  14. 14.
    Martınez-Serrano A, Björklund A (1996) Protection of the neostriatum against excitotoxic damage by neurotrophin-producing, genetically modified neural stem cells. J Neurosci 16(15):4604–4616PubMedGoogle Scholar
  15. 15.
    Dey ND, Bombard MC, Roland BP et al (2010) Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behav Brain Res 214(2):193–200PubMedCrossRefGoogle Scholar
  16. 16.
    Kordower JH, Charles V, Bayer R et al (1994) Intravenous administration of a transferrin receptor antibody-nerve growth factor conjugate prevents the degeneration of cholinergic striatal neurons in a model of Huntington disease. Proc Natl Acad Sci U S A 91(19):9077–9080PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Baquet ZC, Gorski JA, Jones KR (2004) Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J Neurosci 24(17):4250–4258PubMedCrossRefGoogle Scholar
  18. 18.
    Strand A, Baquet Z, Aragaki A et al (2007) Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J Neurosci 27(43):11758–11768PubMedCrossRefGoogle Scholar
  19. 19.
    Altar C, Cai N, Bliven T et al (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389(6653):856–860PubMedCrossRefGoogle Scholar
  20. 20.
    Zuccato C, Cattaneo E (2007) Role of brain-derived neurotrophic factor in Huntington’s disease. Prog Neurobiol 81(5):294–330PubMedCrossRefGoogle Scholar
  21. 21.
    Gauthier LR, Charrin BC, Borrell-Pagès M et al (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118(1):127–138PubMedCrossRefGoogle Scholar
  22. 22.
    Ferrer I, Goutan E, Marin C et al (2000) Brain-derived neurotrophic factor in Huntington disease. Brain Res 866(1–2):257–261PubMedCrossRefGoogle Scholar
  23. 23.
    Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 6(12):919–930PubMedCrossRefGoogle Scholar
  24. 24.
    Giralt A, Rodrigo T, Martin E et al (2009) Brain-derived neurotrophic factor modulates the severity of cognitive alterations induced by mutant huntingtin: involvement of phospholipaseC [gamma] activity and glutamate receptor expression. Neuroscience 158(4):1234–1250PubMedCrossRefGoogle Scholar
  25. 25.
    Canals JM, Pineda JR, Torres-Peraza JF et al (2004) Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J Neurosci 24(35):7727–7739PubMedCrossRefGoogle Scholar
  26. 26.
    Ciammola A, Sassone J, Cannella M et al (2007) Low brain-derived neurotrophic factor (BDNF) levels in serum of Huntington’s disease patients. Am J Med Genet B Neuropsychiatr Genet 144(4):574–577CrossRefGoogle Scholar
  27. 27.
    Kells AP, Fong DM, Dragunow M et al (2004) AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol Ther 9(5):682–688PubMedCrossRefGoogle Scholar
  28. 28.
    Kells A, Henry R, Connor B (2008) AAV–BDNF mediated attenuation of quinolinic acid-induced neuropathology and motor function impairment. Gene Ther 15(13):966–977PubMedCrossRefGoogle Scholar
  29. 29.
    Frim DM, Uhler TA, Short MP et al (1993) Effects of biologically delivered NGF, BDNF and bFGF on striatal excitotoxic lesions. Neuroreport 4(4):367–370PubMedCrossRefGoogle Scholar
  30. 30.
    Ip N, Yancopoulos G (1996) The neurotrophins and CNTF: two families of collaborative neurotrophic factors. Annu Rev Neurosci 19:491–515PubMedCrossRefGoogle Scholar
  31. 31.
    Emerich DF, Lindner MD, Winn SR et al (1996) Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington’s disease. J Neurosci 16(16):5168–5181PubMedGoogle Scholar
  32. 32.
    de Almeida LP, Zala D, Aebischer P et al (2001) Neuroprotective effect of a CNTF-expressing lentiviral vector in the quinolinic acid rat model of Huntington’s disease. Neurobiol Dis 8(3):433–446PubMedCrossRefGoogle Scholar
  33. 33.
    Regulier E, Pereira de Almeida L, Sommer B et al (2002) Dose-dependent neuroprotective effect of ciliary neurotrophic factor delivered via tetracycline-regulated lentiviral vectors in the quinolinic acid rat model of Huntington’s disease. Hum Gene Ther 13(16):1981–1990PubMedCrossRefGoogle Scholar
  34. 34.
    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(8):1177–1188PubMedCrossRefGoogle Scholar
  35. 35.
    Bachoud-Lévi 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(12):1723–1729PubMedCrossRefGoogle Scholar
  36. 36.
    Bloch J, Bachoud-Lévi A, Déglon 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(10):968–975PubMedCrossRefGoogle Scholar
  37. 37.
    Mittoux V, Ouary S, Monville C et al (2002) Corticostriatopallidal neuroprotection by adenovirus-mediated ciliary neurotrophic factor gene transfer in a rat model of progressive striatal degeneration. J Neurosci 22(11):4478–4486PubMedGoogle Scholar
  38. 38.
    Zala D, Bensadoun J, Pereira AL et al (2004) Long-term lentiviral-mediated expression of ciliary neurotrophic factor in the striatum of Huntington’s disease transgenic mice. Exp Neurol 185(1):26–35PubMedCrossRefGoogle Scholar
  39. 39.
    Denovan-Wright E, Attis M, Rodriguez-Lebron E et al (2008) Sustained striatal ciliary neurotrophic factor expression negatively affects behavior and gene expression in normal and R6/1 mice. J Neurosci Res 86(8):1748–1757PubMedCrossRefGoogle Scholar
  40. 40.
    Pochon NAM, Menoud A, Tseng J et al (1997) Neuronal GDNF expression in the adult rat nervous system identified by in situ hybridization. Eur J Neurosci 9(3):463–471PubMedCrossRefGoogle Scholar
  41. 41.
    Akerud P, Alberch J, Eketjäll S et al (1999) Differential effects of glial cell line-derived neurotrophic factor and neurturin on developing and adult substantia nigra dopaminergic neurons. J Neurochem 73(1):70–78PubMedCrossRefGoogle Scholar
  42. 42.
    Airaksinen MS, Saarma M (2002) The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3(5):383–394PubMedCrossRefGoogle Scholar
  43. 43.
    Pineda J, Rubio N, Akerud P et al (2006) Neuroprotection by GDNF-secreting stem cells in a Huntington’s disease model: optical neuroimage tracking of brain-grafted cells. Gene Ther 14(2):118–128PubMedGoogle Scholar
  44. 44.
    Ebert AD, Barber AE, Heins BM et al (2010) Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington’s disease. Exp Neurol 224(1):155–162PubMedCrossRefGoogle Scholar
  45. 45.
    McBride JL, During MJ, Wuu J et al (2003) Structural and functional neuroprotection in a rat model of Huntington’s disease by viral gene transfer of GDNF. Exp Neurol 181(2):213–223PubMedCrossRefGoogle Scholar
  46. 46.
    McBride JL, Ramaswamy S, Gasmi M et al (2006) Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington’s disease. Proc Natl Acad Sci U S A 103(24):9345–9350PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Popovic N, Maingay M, Kirik D et al (2005) Lentiviral gene delivery of GDNF into the striatum of R6/2 Huntington mice fails to attenuate behavioral and neuropathological changes. Exp Neurol 193(1):65–74PubMedCrossRefGoogle Scholar
  48. 48.
    Mangiarini L, Sathasivam K, Seller M et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87(3):493–506PubMedCrossRefGoogle Scholar
  49. 49.
    Kotzbauer PT, Lampe PA, Heuckeroth RO et al (1996) Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 384(6608):467–470PubMedCrossRefGoogle Scholar
  50. 50.
    Alberch J, Perez-Navarro E, Canals J (2002) Neuroprotection by neurotrophins and GDNF family members in the excitotoxic model of Huntington’s disease. Brain Res Bull 57(6):817–822PubMedCrossRefGoogle Scholar
  51. 51.
    Gasmi M, Herzog CD, Brandon EP et al (2007) Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson’s disease. Mol Ther 15(1):62–68PubMedCrossRefGoogle Scholar
  52. 52.
    Ramaswamy S, McBride JL, Herzog CD et al (2007) Neurturin gene therapy improves motor function and prevents death of striatal neurons in a 3-nitropropionic acid rat model of Huntington’s disease. Neurobiol Dis 26(2):375–384PubMedCrossRefGoogle Scholar
  53. 53.
    Ramaswamy S, McBride JL, Han I et al (2009) Intrastriatal CERE-120 (AAV-Neurturin) protects striatal and cortical neurons and delays motor deficits in a transgenic mouse model of Huntington’s disease. Neurobiol Dis 34(1):40–50PubMedCrossRefGoogle Scholar
  54. 54.
    Cardinale A, Biocca S (2008) The potential of intracellular antibodies for therapeutic targeting of protein-misfolding diseases. Trends Mol Med 14(9):373–380PubMedCrossRefGoogle Scholar
  55. 55.
    Fukuchi K, Tahara K, Kim HD et al (2006) Anti-Aβ single-chain antibody delivery via adeno-associated virus for treatment of Alzheimer’s disease. Neurobiol Dis 23(3):502–511PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Levites Y, Jansen K, Smithson LA et al (2006) Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid β, amyloid β40, and amyloid β42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. J Neurosci 26(46):11923–11928PubMedCrossRefGoogle Scholar
  57. 57.
    Wuertzer CA, Sullivan MA, Qiu X et al (2008) CNS delivery of vectored prion-specific single-chain antibodies delays disease onset. Mol Ther 16(3):481–486PubMedCrossRefGoogle Scholar
  58. 58.
    Khoshnan A, Ko J, Patterson PH (2002) Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc Natl Acad Sci U S A 99(2):1002–1007PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Snyder-Keller A, McLear JA, Hathorn T et al (2010) Early or late-stage anti-N-terminal Huntingtin intrabody gene therapy reduces pathological features in B6. HDR6/1 mice. J Neuropathol Exp Neurol 69(10):1078–1085PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Rockabrand E, Slepko N, Pantalone A et al (2007) The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis. Hum Mol Genet 16(1):61–77PubMedCrossRefGoogle Scholar
  61. 61.
    Wang CE, Zhou H, McGuire JR et al (2008) Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol 181(5):803–816PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Qin Z, Wang Y, Sapp E et al (2004) Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J Neurosci 24(1):269–281PubMedCrossRefGoogle Scholar
  63. 63.
    Southwell AL, Khoshnan A, Dunn D et al (2008) Intrabodies binding the proline-rich domains of mutant huntingtin increase its turnover and reduce neurotoxicity. J Neurosci 28(36):9013–9020PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Southwell AL, Ko J, Patterson PH (2009) Intrabody gene therapy ameliorates motor, cognitive and neuropathological symptoms in multiple mouse models of Huntington’s disease. J Neurosci 29(43):13589–13602PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Almeida R, Allshire RC (2005) RNA silencing and genome regulation. Trends Cell Biol 15(5):251–258PubMedCrossRefGoogle Scholar
  66. 66.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297PubMedCrossRefGoogle Scholar
  67. 67.
    Yamamoto A, Lucas JJ, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101(1):57–66PubMedCrossRefGoogle Scholar
  68. 68.
    Paddison PJ, Caudy AA, Bernstein E et al (2002) Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev 16(8):948–958PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Harper SQ, Staber PD, He X et al (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A 102(16):5820–5825PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Rodriguez-Lebron E, Denovan-Wright EM, Nash K et al (2005) Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington’s disease transgenic mice. Mol Ther 12(4):618–633PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Luthi-Carter R, Hanson SA, Strand AD et al (2002) Dysregulation of gene expression in the R6/2 model of polyglutamine disease: parallel changes in muscle and brain. Hum Mol Genet 11(17):1911–1926PubMedCrossRefGoogle Scholar
  72. 72.
    Machida Y, Okada T, Kurosawa M et al (2006) rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse. Biochem Biophys Res Commun 343(1):190–197PubMedCrossRefGoogle Scholar
  73. 73.
    Franich NR, Fitzsimons HL, Fong DM et al (2008) AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease. Mol Ther 16(5):947–956PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Huang B, Schiefer J, Sass C et al (2007) High-capacity adenoviral vector-mediated reduction of huntingtin aggregate load in vitro and in vivo. Hum Gene Ther 18(4):303–311PubMedCrossRefGoogle Scholar
  75. 75.
    Drouet V, Perrin V, Hassig R et al (2009) Sustained effects of nonallele-specific Huntingtin silencing. Ann Neurol 65(3):276–285PubMedCrossRefGoogle Scholar
  76. 76.
    Grondin R, Kaytor MD, Ai Y et al (2012) Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 135(4):1197–1209PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Grimm D, Streetz KL, Jopling CL et al (2006) Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441(7092):537–541PubMedCrossRefGoogle Scholar
  78. 78.
    Olson SD, Kambal A, Pollock K et al (2012) Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington’s disease affected neuronal cells for reduction of huntingtin. Mol Cell Neurosci 49(3):271–281PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Amarzguioui M, Lundberg P, Cantin E et al (2006) Rational design and in vitro and in vivo delivery of Dicer substrate siRNA. Nat Protoc 1(2):508–517PubMedCrossRefGoogle Scholar
  80. 80.
    Judge AD, Bola G, Lee ACH et al (2006) Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Mol Ther 13(3):494–505PubMedCrossRefGoogle Scholar
  81. 81.
    Wang YL, Liu W, Wada E et al (2005) Clinico-pathological rescue of a model mouse of Huntington’s disease by siRNA. Neurosci Res 53(3):241–249PubMedCrossRefGoogle Scholar
  82. 82.
    DiFiglia M, Sena-Esteves M, Chase K et al (2007) Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Natl Acad Sci U S A 104(43):17204–17209PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Stanek LM, Sardi SP, Mastis B et al (2014) Silencing mutant Huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington’s disease. Hum Gene Ther 25:461–474PubMedCrossRefGoogle Scholar
  84. 84.
    Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10(12):1957–1966PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Boden D, Pusch O, Silbermann R et al (2004) Enhanced gene silencing of HIV-1 specific siRNA using microRNA designed hairpins. Nucleic Acids Res 32(3):1154–1158PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Wiznerowicz M, Szulc J, Trono D (2006) Tuning silence: conditional systems for RNA interference. Nat Methods 3(9):682–688PubMedCrossRefGoogle Scholar
  87. 87.
    McBride JL, Boudreau RL, Harper SQ et al (2008) Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci U S A 105(15):5868–5873PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Boudreau RL, McBride JL, Martins I et al (2009) Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Mol Ther 17(6):1053–1063PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    McBride JL, Pitzer MR, Boudreau RL 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(12):2152–2162PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Schwarz DS, Ding H, Kennington L et al (2006) Designing siRNA that distinguish between genes that differ by a single nucleotide. PLoS Genet 2(9):e140PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Zhang Y, Engelman J, Friedlander RM (2009) Allele-specific silencing of mutant Huntington’s disease gene. J Neurochem 108(1):82–90PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Liu W, Kennington LA, Rosas HD et al (2008) Linking SNPs to CAG repeat length in Huntington’s disease patients. Nat Methods 5(11):951–953PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Bilsen PHJ, Jaspers L, Lombardi M et al (2008) Identification and allele-specific silencing of the mutant huntingtin allele in Huntington’s disease patient-derived fibroblasts. Hum Gene Ther 19(7):710–718PubMedCrossRefGoogle Scholar
  94. 94.
    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(9):774–778PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, San Diego, CAGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Pharmacology & Clinical Pharmacology and Centre for Brain Research, Faculty of Medical & Health SciencesUniversity of AucklandAucklandNew Zealand
  2. 2.Department of Pharmacology & Clinical Pharmacology and Centre for Brain Research, Faculty of Medical & Health SciencesUniversity of AucklandAucklandNew Zealand

Personalised recommendations