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Viral Vectors in Primate Research: Examples from Parkinson’s Disease Research

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Book cover Viral Vector Approaches in Neurobiology and Brain Diseases

Part of the book series: Neuromethods ((NM,volume 82))

Abstract

Neurodegenerative diseases, such as Parkinson’s disease (PD), offer unique opportunities for the therapeutic application of viral vector gene transfer. In this chapter, we discuss the current state of viral vector preclinical development in nonhuman primate with special focus on vectors derived from adeno-associated virus (AAV) and lentivirus (LV), as they are the only ones that have reached clinical trials. We also outline desired features for improving the routes of delivery, tropism specificity, and other parameters that influence achievement of successful therapeutic goals.

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Abbreviations

6-OHDA:

6-Hydroxydopamine

AADC:

Aromatic l-amino acid decarboxylase

AAV:

Adeno-associated virus

CNS:

Central nervous system

D1:

Dopamine D1 receptors

D2:

Dopamine D2 receptors

GABA:

γ-Aminobutyric acid

GAD:

Glutamic acid decarboxylase

GCH:

Guanosine triphosphate cyclohydrolase I

GDNF:

Glial cell line-derived neurotrophic factor

GRKs:

G protein coupled receptor

GTPase:

Guanosine triphosphatase

l-DOPA:

l-3,4-Dihydroxyphenylalanine

LID:

l-DOPA-induced dyskinesia

LV:

Lentivirus

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MRI:

Magnetic resonance image

NPH:

Nonhuman primate

PD:

Parkinson’s disease

SN:

Substantia nigra

STN:

Subthalamic nucleus

TH:

Tyrosine hydroxylase

References

  1. Dehay B, Bezard E (2011) New animal models of Parkinson’s disease. Mov Disord 26(7):1198–1205

    Article  PubMed  Google Scholar 

  2. Tuszynski MH (2007) Nerve growth factor gene therapy in Alzheimer disease. Alzheimer Dis Assoc Disord 21(2):179–189

    Article  PubMed  CAS  Google Scholar 

  3. Porras G et al (2012) PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking. J Clin Invest 122(11): 3977–3989

    Article  PubMed  CAS  Google Scholar 

  4. Ahmed MR et al (2010) Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson’s disease. Sci Transl Med 2(28):28ra28

    Article  PubMed  Google Scholar 

  5. Meissner WG et al (2011) Priorities in Parkinson’s disease research. Nat Rev Drug Discov 10(5):377–393

    Article  PubMed  CAS  Google Scholar 

  6. Tuszynski MH et al (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 11(5):551–555

    Article  PubMed  CAS  Google Scholar 

  7. Marks WJ Jr et al (2010) Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 9(12):1164–1172

    Article  PubMed  CAS  Google Scholar 

  8. Lundberg C et al (2008) Applications of lentiviral vectors for biology and gene therapy of neurological disorders. Curr Gene Ther 8(6):461–473

    Article  PubMed  CAS  Google Scholar 

  9. Kordower JH et al (1999) Lentiviral gene transfer to the nonhuman primate brain. Exp Neurol 160(1):1–16

    Article  PubMed  CAS  Google Scholar 

  10. Kordower JH (2003) In vivo gene delivery of glial cell line—derived neurotrophic factor for Parkinson’s disease. Ann Neurol 53(Suppl 3):S120–S132, discussion S132–4

    Article  PubMed  CAS  Google Scholar 

  11. Gash DM, Gerhardt GA, Hoffer BJ (1998) Effects of glial cell line-derived neurotrophic factor on the nigrostriatal dopamine system in rodents and nonhuman primates. Adv Pharmacol 42:911–915

    Article  PubMed  CAS  Google Scholar 

  12. Kordower JH et al (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290(5492):767–773

    Article  PubMed  CAS  Google Scholar 

  13. Palfi S et al (2002) Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration. J Neurosci 22(12):4942–4954

    PubMed  CAS  Google Scholar 

  14. Jarraya B et al (2009) Dopamine gene therapy for Parkinson’s disease in a nonhuman primate without associated dyskinesia. Sci Transl Med 1(2):2ra4

    Article  PubMed  Google Scholar 

  15. Bezard E, Brotchie JM, Gross CE (2001) Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci 2(8):577–588

    Article  PubMed  CAS  Google Scholar 

  16. Fahn S (2006) Levodopa in the treatment of Parkinson’s disease. J Neural Transm Suppl (71):1–15

    Google Scholar 

  17. Guigoni C, Doudnikoff E, Li Q, Bloch B, Bezard E (2007) Altered D(1) dopamine receptor trafficking in parkinsonian and dyskinetic non-human primates. Neurobiol Dis 26(2):452–463

    Article  PubMed  CAS  Google Scholar 

  18. Bezard E et al (2005) L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain. Neurobiol Dis 18(2): 323–335

    Article  PubMed  CAS  Google Scholar 

  19. Fasano S et al (2010) Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia. Proc Natl Acad Sci USA 107(50):21824–21829

    Article  PubMed  CAS  Google Scholar 

  20. Pearce RK, Jackson M, Smith L, Jenner P, Marsden CD (1995) Chronic L-DOPA administration induces dyskinesias in the 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-treated common marmoset (Callithrix Jacchus). Mov Disord 10(6):731–740

    Article  PubMed  CAS  Google Scholar 

  21. Gold SJ et al (2007) RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson’s disease. J Neurosci 27(52):14338–14348

    Article  PubMed  CAS  Google Scholar 

  22. Nash JE, Johnston TH, Collingridge GL, Garner CC, Brotchie JM (2005) Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson’s disease and L-DOPA-induced dyskinesia. FASEB J 19(6):583–585

    PubMed  CAS  Google Scholar 

  23. Palfi S et al (2007) Expression of mutated huntingtin fragment in the putamen is sufficient to produce abnormal movement in non-human primates. Mol Ther 15(8): 1444–1451

    Article  PubMed  CAS  Google Scholar 

  24. Kwon I, Schaffer DV (2008) Designer gene delivery vectors: molecular engineering and evolution of adeno-associated viral vectors for enhanced gene transfer. Pharm Res 25(3): 489–499

    Article  PubMed  CAS  Google Scholar 

  25. Zhang H, Xie J, Xie Q, Wilson JM, Gao G (2009) Adenovirus-adeno-associated virus hybrid for large-scale recombinant adeno-associated virus production. Hum Gene Ther 20(9):922–929

    Article  PubMed  CAS  Google Scholar 

  26. Gao G, Vandenberghe LH, Wilson JM (2005) New recombinant serotypes of AAV vectors. Curr Gene Ther 5(3):285–297

    Article  PubMed  CAS  Google Scholar 

  27. Gao GP et al (2002) Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci USA 99(18):11854–11859

    Article  PubMed  CAS  Google Scholar 

  28. Vandenberghe LH, Wilson JM, Gao G (2009) Tailoring the AAV vector capsid for gene therapy. Gene Ther 16(3):311–319

    Article  PubMed  CAS  Google Scholar 

  29. Bankiewicz KS et al (2000) Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol 164(1):2–14

    Article  PubMed  CAS  Google Scholar 

  30. Bankiewicz KS et al (2006) Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC. Mol Ther 14(4):564–570

    Article  PubMed  CAS  Google Scholar 

  31. Forsayeth JR et al (2006) A dose-ranging study of AAV-hAADC therapy in Parkinsonian monkeys. Mol Ther 14(4):571–577

    Article  PubMed  CAS  Google Scholar 

  32. Hadaczek P et al (2010) Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol Ther 18(8):1458–1461

    Article  PubMed  CAS  Google Scholar 

  33. Muramatsu S et al (2002) Behavioral recovery in a primate model of Parkinson’s disease by triple transduction of striatal cells with adeno-associated viral vectors expressing dopamine-synthesizing enzymes. Hum Gene Ther 13(3):345–354

    Article  PubMed  CAS  Google Scholar 

  34. Lozano AM, Dostrovsky J, Chen R, Ashby P (2002) Deep brain stimulation for Parkinson’s disease: disrupting the disruption. Lancet Neurol 1(4):225–231

    Article  PubMed  Google Scholar 

  35. Emborg ME et al (2007) Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism. J Cereb Blood Flow Metab 27(3):501–509

    Article  PubMed  CAS  Google Scholar 

  36. Feigin A et al (2007) Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson’s disease. Proc Natl Acad Sci USA 104(49):19559–19564

    Article  PubMed  CAS  Google Scholar 

  37. LeWitt PA et al (2011) AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 10(4):309–319

    Article  PubMed  CAS  Google Scholar 

  38. Eslamboli A et al (2005) Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant adeno-associated viral vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson’s disease. J Neurosci 25(4):769–777

    Article  PubMed  CAS  Google Scholar 

  39. Kells AP et al (2010) Regeneration of the MPTP-lesioned dopaminergic system after convection-enhanced delivery of AAV2-GDNF. J Neurosci 30(28):9567–9577

    Article  PubMed  CAS  Google Scholar 

  40. Kordower JH et al (2006) Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys. Ann Neurol 60(6):706–715

    Article  PubMed  CAS  Google Scholar 

  41. Berton O et al (2009) Striatal overexpression of DeltaJunD resets L-DOPA-induced dyskinesia in a primate model of Parkinson disease. Biol Psychiatry 66(6):554–561

    Article  PubMed  CAS  Google Scholar 

  42. Ciron C et al (2009) Human alpha-iduronidase gene transfer mediated by adeno-associated virus types 1, 2, and 5 in the brain of nonhuman primates: vector diffusion and biodistribution. Hum Gene Ther 20(4):350–360

    Article  PubMed  CAS  Google Scholar 

  43. McFarland NR, Lee JS, Hyman BT, McLean PJ (2009) Comparison of transduction efficiency of recombinant AAV serotypes 1, 2, 5, and 8 in the rat nigrostriatal system. J Neurochem 109(3):838–845

    Article  PubMed  CAS  Google Scholar 

  44. Taymans JM et al (2007) Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum Gene Ther 18(3):195–206

    Article  PubMed  CAS  Google Scholar 

  45. Colle MA et al (2010) Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate. Hum Mol Genet 19(1):147–158

    Article  PubMed  CAS  Google Scholar 

  46. Dodiya HB et al (2010) Differential transduction following basal ganglia administration of distinct pseudotyped AAV capsid serotypes in nonhuman primates. Mol Ther 18(3):579–587

    Article  PubMed  CAS  Google Scholar 

  47. Hadaczek P et al (2009) Transduction of nonhuman primate brain with adeno-associated virus serotype 1: vector trafficking and immune response. Hum Gene Ther 20(3):225–237

    Article  PubMed  CAS  Google Scholar 

  48. Markakis EA et al (2010) Comparative transduction efficiency of AAV vector serotypes 1–6 in the substantia nigra and striatum of the primate brain. Mol Ther 18(3):588–593

    Article  PubMed  CAS  Google Scholar 

  49. Sanchez CE et al (2011) Recombinant adeno-associated virus type 2 pseudotypes: comparing safety, specificity, and transduction efficiency in the primate striatum. Laboratory investigation. J Neurosurg 114(3):672–680

    Article  PubMed  Google Scholar 

  50. Yasuda T et al (2007) Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates. Neuroscience 144(2):743–753

    Article  PubMed  CAS  Google Scholar 

  51. Inagaki K et al (2007) DNA palindromes with a modest arm length of greater, similar 20 base pairs are a significant target for recombinant adeno-associated virus vector integration in the liver, muscles, and heart in mice. J Virol 81(20):11290–11303

    Article  PubMed  CAS  Google Scholar 

  52. Zhang H et al (2011) Several rAAV vectors efficiently cross the blood–brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. Mol Ther 19(8):1440–1448

    Article  PubMed  CAS  Google Scholar 

  53. Foust KD et al (2009) Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 27(1):59–65

    Article  PubMed  CAS  Google Scholar 

  54. Duque S et al (2009) Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther 17(7):1187–1196

    Article  PubMed  CAS  Google Scholar 

  55. Dominguez E et al (2011) Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet 20(4):681–693

    Article  PubMed  CAS  Google Scholar 

  56. Foust KD et al (2010) Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 28(3):271–274

    Article  PubMed  CAS  Google Scholar 

  57. Spampanato C et al (2011) Efficacy of a combined intracerebral and systemic gene delivery approach for the treatment of a severe lysosomal storage disorder. Mol Ther 19(5):860–869

    Article  PubMed  CAS  Google Scholar 

  58. Gray SJ et al (2011) Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Ther 19(6):1058–1069

    Article  PubMed  CAS  Google Scholar 

  59. Bevan AK et al (2011) Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol Ther 19(11):1971–1980

    Article  PubMed  CAS  Google Scholar 

  60. Samaranch L et al (2012) Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum Gene Ther 23(4):382–389

    Article  PubMed  CAS  Google Scholar 

  61. Dehay B, Dalkara D, Dovero S, Li Q, Bezard E (2012) Systemic scAAV9 variant mediates brain transduction in newborn rhesus macaques. Sci Rep 2:253

    Article  PubMed  Google Scholar 

  62. Mattar CN et al (2013) Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems. Gene Ther 20(1):69–83

    Article  PubMed  CAS  Google Scholar 

  63. Federici T et al (2012) Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther 19(8):852–859

    Article  PubMed  CAS  Google Scholar 

  64. Xie J et al (2011) MicroRNA-regulated, systemically delivered rAAV9: a step closer to CNS-restricted transgene expression. Mol Ther 19(3):526–535

    Article  PubMed  CAS  Google Scholar 

  65. Asokan A, Schaffer DV, Samulski RJ (2012) The AAV vector toolkit: poised at the clinical crossroads. Mol Ther 20(4):699–708

    Article  PubMed  CAS  Google Scholar 

  66. Gray SJ et al (2010) Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood–brain barrier (BBB). Mol Ther 18(3):570–578

    Article  PubMed  CAS  Google Scholar 

  67. Asokan A et al (2010) Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol 28(1):79–82

    Article  PubMed  CAS  Google Scholar 

  68. Gray SJ, Nagabhushan Kalburgi S, McCown TJ, Jude Samulski R (2013) Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther 20(4):450–459

    Article  PubMed  CAS  Google Scholar 

  69. Bielicki J, McIntyre C, Anson DS (2010) Comparison of ventricular and intravenous lentiviral-mediated gene therapy for murine MPS VII. Mol Genet Metab 101(4):370–382

    Article  PubMed  CAS  Google Scholar 

  70. Passini MA et al (2003) Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of beta-glucuronidase-deficient mice. J Virol 77(12):7034–7040

    Article  PubMed  CAS  Google Scholar 

  71. Regev L, Ezrielev E, Gershon E, Gil S, Chen A (2010) Genetic approach for intracerebroventricular delivery. Proc Natl Acad Sci USA 107(9):4424–4429

    Article  PubMed  CAS  Google Scholar 

  72. Lam MF, Thomas MG, Lind CR (2011) Neurosurgical convection-enhanced delivery of treatments for Parkinson’s disease. J Clin Neurosci 18(9):1163–1167

    Article  PubMed  Google Scholar 

  73. Bobo RH et al (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91(6):2076–2080

    Article  PubMed  CAS  Google Scholar 

  74. Cunningham J et al (2008) Biodistribution of adeno-associated virus type-2 in nonhuman primates after convection-enhanced delivery to brain. Mol Ther 16(7):1267–1275

    Article  PubMed  CAS  Google Scholar 

  75. Fiandaca MS, Forsayeth JR, Dickinson PJ, Bankiewicz KS (2008) Image-guided convection-enhanced delivery platform in the treatment of neurological diseases. Neurotherapeutics 5(1):123–127

    Article  PubMed  Google Scholar 

  76. Salegio EA, Samaranch L, Kells AP, Forsayeth J, Bankiewicz K (2012) Guided delivery of adeno-associated viral vectors into the primate brain. Adv Drug Deliv Rev 64(7):598–604

    Article  PubMed  CAS  Google Scholar 

  77. Chen ZJ et al (2004) A realistic brain tissue phantom for intraparenchymal infusion studies. J Neurosurg 101(2):314–322

    Article  PubMed  Google Scholar 

  78. Fatouros PP et al (2006) In vitro and in vivo imaging studies of a new endohedral metallofullerene nanoparticle. Radiology 240(3):756–764

    Article  PubMed  Google Scholar 

  79. Krauze MT et al (2005) Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 103(5): 923–929

    Article  PubMed  Google Scholar 

  80. Rosenbluth KH et al (2011) Design of an in-dwelling cannula for convection-enhanced delivery. J Neurosci Methods 196(1):118–123

    Article  PubMed  Google Scholar 

  81. Sanftner LM et al (2005) AAV2-mediated gene delivery to monkey putamen: evaluation of an infusion device and delivery parameters. Exp Neurol 194(2):476–483

    Article  PubMed  CAS  Google Scholar 

  82. Saito R et al (2005) Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain. Exp Neurol 196(2):381–389

    Article  PubMed  CAS  Google Scholar 

  83. Yin D et al (2011) Optimal region of the putamen for image-guided convection-enhanced delivery of therapeutics in human and non-human primates. Neuroimage 54(Suppl 1):S196–S203

    Article  PubMed  CAS  Google Scholar 

  84. Eberling JL et al (2008) Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 70(21):1980–1983

    Article  PubMed  CAS  Google Scholar 

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Porras, G., Dehay, B., Bezard, E. (2014). Viral Vectors in Primate Research: Examples from Parkinson’s Disease Research. In: Brambilla, R. (eds) Viral Vector Approaches in Neurobiology and Brain Diseases. Neuromethods, vol 82. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-610-8_17

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  • DOI: https://doi.org/10.1007/978-1-62703-610-8_17

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