Current Neurology and Neuroscience Reports

, Volume 11, Issue 4, pp 362–370

An Update on Gene Therapy in Parkinson’s Disease

Article

Abstract

Gene therapy for Parkinson’s disease (PD) may offer an alternative to current pharmacologic and surgical treatments; the former are limited by motor complications and non-motor adverse effects, and both by lack of neuroprotection. Three main strategies under investigation using gene transfer for targeted protein expression include improving availability of dopamine to the striatum with more continuous delivery, reducing activity in the subthalamic nucleus by locally inducing γ-aminobutyric acid expression, or protecting and restoring nigrostriatal neuronal function with trophic factor expression. This review summarizes the components of gene therapy for PD, the preclinical rationale for each strategy, data from the most recently published clinical trials using four different vector-gene agents, and challenges in moving gene therapy forward. Thus far, safety data from phase 1 trials have been encouraging for all four agents and one phase 2 trial suggests modest symptomatic efficacy, but definitive conclusions on efficacy cannot yet be drawn.

Keywords

Parkinson’s disease Gene therapy Gene transfer Investigational therapies Viral vectors Surgical treatment Aromatic L-amino acid decarboxylase (AADC) Tyrosine hydroxylase (TH) Guanosine 5’-triphosphate cyclohydrolase 1 (CH1) Subthalamic nucleus Neurturin (NTN) Neurotrophic factors Continuous dopamine delivery Neuroprotection 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev. 1966;18:925–64.PubMedGoogle Scholar
  2. 2.
    Schapira AH. Etiology of Parkinson's disease. Neurology. 2006;66:S10–23.PubMedGoogle Scholar
  3. 3.
    Marsden CD, Parkes JD. Success and problems of long-term levodopa therapy in Parkinson's disease. Lancet. 1977;8007:345–9.CrossRefGoogle Scholar
  4. 4.
    Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24:197–211.PubMedCrossRefGoogle Scholar
  5. 5.
    Lang AE, Lozano AM. Parkinson's disease. First of two parts. N Engl J Med. 1998;339:1044–53.PubMedCrossRefGoogle Scholar
  6. 6.
    Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med. 1998;339:1130–43.PubMedCrossRefGoogle Scholar
  7. 7.
    Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology. 2009;72:S1–S136.PubMedCrossRefGoogle Scholar
  8. 8.
    Nutt JG, Holford NH. The response to levodopa in Parkinson's disease: imposing pharmacological law and order. Ann Neurol. 1996;39:561–73.PubMedCrossRefGoogle Scholar
  9. 9.
    Jankovic J. Complications and limitations of drug therapy for Parkinson's disease. Neurology. 2000;55:S2–6.PubMedGoogle Scholar
  10. 10.
    Deep Brain Stimulation for Parkinson's Disease Study Group. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease. N Engl J Med. 2001;345:956–63.CrossRefGoogle Scholar
  11. 11.
    Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease. N Engl J Med. 2010;362:2077–91.PubMedCrossRefGoogle Scholar
  12. 12.
    Lang AE, Lozano AM, Montgomery E, et al. Posteroventral medial pallidotomy in advanced Parkinson's disease. N Engl J Med. 1997;337:1036–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Eriksdotter Jonhagen M, Nordberg A, Amberla K, et al. Intracerebroventricular infusion of nerve growth factor in three patients with Alzheimer's disease. Dement Geriatr Cogn Disord. 1998;9:246–57.PubMedCrossRefGoogle Scholar
  14. 14.
    Nutt JG, Burchiel KJ, Comella CL, et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology. 2003;60:69–73.PubMedGoogle Scholar
  15. 15.
    Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006;59:459–66.PubMedCrossRefGoogle Scholar
  16. 16.
    Schnepp BC, Clark KR, Klemanski DL, et al. Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J Virol. 2003;77:3495–504.PubMedCrossRefGoogle Scholar
  17. 17.
    Fan DS, Ogawa M, Fujimoto KI, et al. Behavioral recovery in 6-hydroxydopamine-lesioned rats by cotransduction of striatum with tyrosine hydroxylase and aromatic L-amino acid decarboxylase genes using two separate adeno-associated virus vectors. Hum Gene Ther. 1998;9:2527–35.PubMedCrossRefGoogle Scholar
  18. 18.
    Shen Y, Muramatsu SI, Ikeguchi K, et al. Triple transduction with adeno-associated virus vectors expressing tyrosine hydroxylase, aromatic-L-amino-acid decarboxylase, and GTP cyclohydrolase I for gene therapy of Parkinson's disease. Hum Gene Ther. 2000;11:1509–19.PubMedCrossRefGoogle Scholar
  19. 19.
    Bankiewicz KS, Forsayeth J, Eberling JL, et al. Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC. Mol Ther. 2006;14:564–70.PubMedCrossRefGoogle Scholar
  20. 20.
    Kaplitt MG, Leone P, Samulski RJ, et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet. 1994;8:148–54.PubMedCrossRefGoogle Scholar
  21. 21.
    Du B, Wu P, Boldt-Houle DM, Terwilliger EF. Efficient transduction of human neurons with an adeno-associated virus vector. Gene Ther. 1996;3:254–61.PubMedGoogle Scholar
  22. 22.
    Azzouz M, Martin-Rendon E, Barber RD, et al. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease. J Neurosci. 2002;22:10302–12.PubMedGoogle Scholar
  23. 23.
    Mitrophanous K, Yoon S, Rohll J, et al. Stable gene transfer to the nervous system using a non-primate lentiviral vector. Gene Ther. 1999;6:1808–18.PubMedCrossRefGoogle Scholar
  24. 24.
    Choi-Lundberg DL, Lin Q, Chang YN, et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science. 1997;275:838–41.PubMedCrossRefGoogle Scholar
  25. 25.
    Bilang-Bleuel A, Revah F, Colin P, et al. Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease. Proc Natl Acad Sci U S A. 1997;94:8818–23.PubMedCrossRefGoogle Scholar
  26. 26.
    During MJ, Naegele JR, O'Malley KL, Geller AI. Long-term behavioral recovery in parkinsonian rats by an HSV vector expressing tyrosine hydroxylase. Science. 1994;266:1399–403.PubMedCrossRefGoogle Scholar
  27. 27.
    Isacson O. Behavioral effects and gene delivery in a rat model of Parkinson's disease. Science. 1995;269:856–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80:148–58.PubMedCrossRefGoogle Scholar
  29. 29.
    Lloyd KG, Davidson L, Hornykiewicz O. The neurochemistry of Parkinson's disease: effect of L-dopa therapy. J Pharmacol Exp Ther. 1975;195:453–64.PubMedGoogle Scholar
  30. 30.
    Nagatsu T, Sawada M. Biochemistry of postmortem brains in Parkinson's disease: historical overview and future prospects. J Neural Transm Suppl. 2007;72:113–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Leff SE, Spratt SK, Snyder RO, Mandel RJ. Long-term restoration of striatal L-aromatic amino acid decarboxylase activity using recombinant adeno-associated viral vector gene transfer in a rodent model of Parkinson's disease. Neuroscience. 1999;92:185–96.PubMedCrossRefGoogle Scholar
  32. 32.
    Bankiewicz KS, Eberling JL, Kohutnicka M, et al. 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. 2000;164:2–14.PubMedCrossRefGoogle Scholar
  33. 33.
    Eberling JL, Jagust WJ, Christine CW, et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology. 2008;70:1980–3.PubMedCrossRefGoogle Scholar
  34. 34.
    • Christine CW, Starr PA, Larson PS, et al.: Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009, 73:1662–1669. This study reports phase 1 data to support safety of AAV-AADC and possible efficacy in improving motor function in moderate to advance PD patients and includes [ 18 F]FMT-PET demonstration of dose-responsive bioactivity.PubMedCrossRefGoogle Scholar
  35. 35.
    Bankiewicz KS, Daadi M, Pivirotto P, et al. Focal striatal dopamine may potentiate dyskinesias in parkinsonian monkeys. Exp Neurol. 2006;197:363–72.PubMedCrossRefGoogle Scholar
  36. 36.
    Thobois S, Ardouin C, Lhommee E, et al. Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation. Brain. 2010;133:1111–27.PubMedCrossRefGoogle Scholar
  37. 37.
    Elsworth JD, Roth RH. Dopamine synthesis, uptake, metabolism, and receptors: relevance to gene therapy of Parkinson's disease. Exp Neurol. 1997;144:4–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Kumer SC, Vrana KE. Intricate regulation of tyrosine hydroxylase activity and gene expression. J Neurochem. 1996;67:443–62.PubMedCrossRefGoogle Scholar
  39. 39.
    Nagatsu T, Ichinose H. GTP cyclohydrolase I gene, dystonia, juvenile parkinsonism, and Parkinson's disease. J Neural Transm Suppl. 1997;49:203–9.PubMedGoogle Scholar
  40. 40.
    Olanow CW, Obeso JA. Preventing levodopa-induced dyskinesias. Ann Neurol. 2000;47:S167–76.PubMedGoogle Scholar
  41. 41.
    Muramatsu S, Fujimoto K, Ikeguchi K, et al. 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. 2002;13:345–54.PubMedCrossRefGoogle Scholar
  42. 42.
    Jarraya B, Boulet S, Ralph GS, et al.: Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia. Sci Transl Med 2009, 1:2ra4.Google Scholar
  43. 43.
    Bjorklund A, Bjorklund T, Kirik D: Gene therapy for dopamine replacement in Parkinson's disease. Sci Transl Med 2009, 1:2 ps.Google Scholar
  44. 44.
    Chen L, Ding Y, Cagniard B, et al. Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice. J Neurosci. 2008;28:425–33.PubMedCrossRefGoogle Scholar
  45. 45.
    Hamani C, Saint-Cyr JA, Fraser J, et al. The subthalamic nucleus in the context of movement disorders. Brain. 2004;127:4–20.PubMedCrossRefGoogle Scholar
  46. 46.
    Bergman H, Wichmann T, DeLong MR. Reversal of experimental Parkinsonism by lesions of the subthalamic nucleus. Science. 1990;249:1436–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Luo J, Kaplitt MG, Fitzsimons HL, et al. Subthalamic GAD gene therapy in a Parkinson's disease rat model. Science. 2002;298:425–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Lee B, Lee H, Nam YR, et al. Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models. Gene Ther. 2005;12:1215–22.PubMedCrossRefGoogle Scholar
  49. 49.
    Emborg ME, Carbon M, Holden JE, et al. Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism. J Cereb Blood Flow Metab. 2007;27:501–9.PubMedCrossRefGoogle Scholar
  50. 50.
    • Kaplitt MG, Feigin A, Tang C, et al.: Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet 2007, 369:2097–2105. This study provides 1-year phase 1 safety data for AAV-GAD, demonstrates possible clinical efficacy, and functional imaging results support bioactivity.PubMedCrossRefGoogle Scholar
  51. 51.
    •• LeWitt PA, Rezai AR, Leehey MA, et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double blind, sham-surgery controlled, randomised trial. Lancet Neurol 2011, doi:10.1016/S1474-4422(11)70039-4. This is the first phase 2 randomised sham-controlled gene therapy study to successfully meet the primary outcome measure of improvement of off-medication UPDRS motor score at 6 months compared to controls.
  52. 52.
    Hefti F, Hartikka J, Knusel B. Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases. Neurobiol Aging. 1989;10:515–33.PubMedCrossRefGoogle Scholar
  53. 53.
    Kotzbauer PT, Lampe PA, Heuckeroth RO, et al. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature. 1996;384:467–70.PubMedCrossRefGoogle Scholar
  54. 54.
    Horger BA, Nishimura MC, Armanini MP, et al. Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. J Neurosci. 1998;18:4929–37.PubMedGoogle Scholar
  55. 55.
    Dass B, Olanow CW, Kordower JH. Gene transfer of trophic factors and stem cell grafting as treatments for Parkinson's disease. Neurology. 2006;66:S89–S103.PubMedGoogle Scholar
  56. 56.
    Palfi S, Leventhal L, Chu Y, et al. Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration. J Neurosci. 2002;22:4942–54.PubMedGoogle Scholar
  57. 57.
    Hoane MR, Gulwadi AG, Morrison S, et al. Differential in vivo effects of neurturin and glial cell-line-derived neurotrophic factor. Exp Neurol. 1999;160:235–43.PubMedCrossRefGoogle Scholar
  58. 58.
    Kordower JH, Emborg ME, Bloch J, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science. 2000;290:767–73.PubMedCrossRefGoogle Scholar
  59. 59.
    Rosenblad C, Kirik D, Devaux B, et al. Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson's disease after administration into the striatum or the lateral ventricle. Eur J Neurosci. 1999;11:1554–66.PubMedCrossRefGoogle Scholar
  60. 60.
    Kirik D, Georgievska B, Bjorklund A. Localized striatal delivery of GDNF as a treatment for Parkinson disease. Nat Neurosci. 2004;7:105–10.PubMedCrossRefGoogle Scholar
  61. 61.
    Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003;9:589–95.PubMedCrossRefGoogle Scholar
  62. 62.
    Peterson AL, Nutt JG. Treatment of Parkinson's disease with trophic factors. Neurotherapeutics. 2008;5:270–80.PubMedCrossRefGoogle Scholar
  63. 63.
    Tseng JL, Bruhn SL, Zurn AD, Aebischer P. Neurturin protects dopaminergic neurons following medial forebrain bundle axotomy. Neuroreport. 1998;9:1817–22.PubMedCrossRefGoogle Scholar
  64. 64.
    Oiwa Y, Yoshimura R, Nakai K, Itakura T. Dopaminergic neuroprotection and regeneration by neurturin assessed by using behavioral, biochemical and histochemical measurements in a model of progressive Parkinson's disease. Brain Res. 2002;947:271–83.PubMedCrossRefGoogle Scholar
  65. 65.
    Gasmi M, Herzog CD, Brandon EP, et al. Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson's disease. Mol Ther. 2007;15:62–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Gasmi M, Brandon EP, Herzog CD, et al. AAV2-mediated delivery of human neurturin to the rat nigrostriatal system: long-term efficacy and tolerability of CERE-120 for Parkinson's disease. Neurobiol Dis. 2007;27:67–76.PubMedCrossRefGoogle Scholar
  67. 67.
    Herzog CD, Dass B, Gasmi M, et al. Transgene expression, bioactivity, and safety of CERE-120 (AAV2-neurturin) following delivery to the monkey striatum. Mol Ther. 2008;16:1737–44.PubMedCrossRefGoogle Scholar
  68. 68.
    Herzog CD, Brown L, Gammon D, et al. Expression, bioactivity, and safety 1 year after adeno-associated viral vector type 2-mediated delivery of neurturin to the monkey nigrostriatal system support cere-120 for Parkinson's disease. Neurosurgery. 2009;64:602–12.PubMedCrossRefGoogle Scholar
  69. 69.
    Kordower JH, Herzog CD, Dass B, et al. Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys. Ann Neurol. 2006;60:706–15.PubMedCrossRefGoogle Scholar
  70. 70.
    Herzog CD, Dass B, Holden JE, et al. Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys. Mov Disord. 2007;22:1124–32.PubMedCrossRefGoogle Scholar
  71. 71.
    • Marks WJ, Jr., Ostrem JL, Verhagen L, et al.: Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial. Lancet Neurol 2008, 7:400–408. This study demonstrates a favorable safety profile and possible efficacy for AAV2-NTN, which supported continued investigation with a sham-controlled phase 2 trial.PubMedCrossRefGoogle Scholar
  72. 72.
    •• Marks WJ, Jr., Bartus RT, Siffert J, et al.: Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol 2010, 9:1164–1172. This is the first randomized, placebo-controlled study using a gene therapy approach for PD published. The active treatment group failed to show superiority in motor function to the sham surgery control group at 1 year, but those followed blindly for 15 to 18 months had significantly lower UPDRS scores than controls. These results have led to a second phase 1/2 trial to address targeting, dose, and follow-up issues.PubMedCrossRefGoogle Scholar
  73. 73.
    Bartus RT, Herzog CD, Chu Y, et al.: Bioactivity of AAV2-neurturin gene therapy (CERE-120): Differences between Parkinson's disease and nonhuman primate brains. Mov Disord. 2011;26:27–36.Google Scholar
  74. 74.
    Kohn DB, Sadelain M, Glorioso JC. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer. 2003;3:477–88.PubMedCrossRefGoogle Scholar
  75. 75.
    Kim SY, Holloway RG, Frank S, et al. Volunteering for early phase gene transfer research in Parkinson disease. Neurology. 2006;66:1010–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Goetz CG, Wuu J, McDermott MP, et al. Placebo response in Parkinson's disease: comparisons among 11 trials covering medical and surgical interventions. Mov Disord. 2008;23:690–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Diederich NJ, Goetz CG. The placebo treatments in neurosciences: new insights from clinical and neuroimaging studies. Neurology. 2008;71:677–84.PubMedCrossRefGoogle Scholar
  78. 78.
    Richards M, Marder K, Cote L, Mayeux R. Interrater reliability of the Unified Parkinson's Disease Rating Scale motor examination. Mov Disord. 1994;9:89–91.PubMedCrossRefGoogle Scholar
  79. 79.
    Metman LV, Myre B, Verwey N, et al. Test-retest reliability of UPDRS-III, dyskinesia scales, and timed motor tests in patients with advanced Parkinson's disease: an argument against multiple baseline assessments. Mov Disord. 2004;19:1079–84.PubMedCrossRefGoogle Scholar
  80. 80.
    Goetz CG, Stebbins GT, Wolff D, et al. Testing objective measures of motor impairment in early Parkinson’s disease: feasibility study of an At-Home Testing Device. Mov Disord. 2009;24:551–56.PubMedCrossRefGoogle Scholar
  81. 81.
    Bjorklund T, Carlsson T, Cederfjall EA, et al. Optimized adeno-associated viral vector-mediated striatal DOPA delivery restores sensorimotor function and prevents dyskinesias in a model of advanced Parkinson's disease. Brain. 2010;133:496–511.PubMedCrossRefGoogle Scholar
  82. 82.
    Carlsson T, Winkler C, Burger C, et al. Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors. Brain. 2005;128:559–69.PubMedCrossRefGoogle Scholar
  83. 83.
    Biju K, Zhou Q, Li G, et al. Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: a therapeutic strategy for Parkinson's disease. Mol Ther. 2010;18:1536–44.PubMedCrossRefGoogle Scholar
  84. 84.
    Glavaski-Joksimovic A, Virag T, Mangatu TA, et al. Glial cell line-derived neurotrophic factor-secreting genetically modified human bone marrow-derived mesenchymal stem cells promote recovery in a rat model of Parkinson's disease. J Neurosci Res. 2010;88:2669–81.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2011

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Parkinson’s Disease Research, Education, and Clinical CenterSan Francisco Veterans Affairs Medical CenterSan FranciscoUSA

Personalised recommendations