, Volume 11, Issue 1, pp 60–67

Gene-based Therapies in Parkinson’s Disease



Parkinson’s disease (PD) is a progressive neurological disorder characterized primarily by the degeneration of nigrostriatal dopaminergic neurons and diminution of the neurotransmitter dopamine. Though dopamine replacement therapies such as levodopa can improve the symptoms of PD, the benefits may be overshadowed by side effects and the onset of symptoms not responsive to dopaminergic treatments (e.g., autonomic symptoms, gait and balance problems, and cognitive impairment). Furthermore, no therapies have proven to slow the neurodegenerative process. Novel approaches to address these difficult problems, and others, are being sought. Over the last decade, several innovative gene therapies for PD have entered human clinical trials in an effort to address both symptomatic and potential disease-modifying effects. Though the results of these trials have been mixed, the therapies have generally been safe and well-tolerated, suggesting gene therapy may be a viable treatment for PD in the future. This article will review past and current clinical trials of gene therapies for PD. In addition, novel preclinical approaches to gene therapy for PD will be described.


Parkinson’s disease Gene therapy Clinical trials Neurodegeneration Dopamine 

Supplementary material

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  1. 1.
    Witt J, Marks WJ. An update on gene therapy in Parkinson’s disease. Curr Neurol Neurosci Rep 2011;11:362–370.PubMedCrossRefGoogle Scholar
  2. 2.
    Akerud P, Canals JM, Snyder EY, Arenas E. Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson’s disease. J Neurosci 2001;21:8108–8118.PubMedGoogle Scholar
  3. 3.
    Park KW, Eglitis MA, Mouradian MM. Protection of nigral neurons by GDNF-engineered marrow cell transplantation. Neurosci Res 2001;40:315–323.PubMedCrossRefGoogle Scholar
  4. 4.
    Cunningham LA, Su C. Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson’s disease. Exp Neurol 2002;174:230–242.PubMedCrossRefGoogle Scholar
  5. 5.
    Manfredsson FP, Bloom DC, Mandel RJ. Regulated protein expression for in vivo gene therapy for neurological disorders: progress, strategies, and issues. Neurobiol Dis 2012;48:212–221.PubMedCrossRefGoogle Scholar
  6. 6.
    Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 2003;348:255–256.PubMedCrossRefGoogle Scholar
  7. 7.
    McCarty DM, Young SM, Jr, Samulski RJ. Integration of adeno-associated virus (AAV) and recombinant AAV vectors. Annu Rev Genet 2004;38:819–845.PubMedCrossRefGoogle Scholar
  8. 8.
    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;80:148–158.PubMedCrossRefGoogle Scholar
  9. 9.
    McPhee SW, Janson CG, Li C, et al. Immune responses to AAV in a phase I study for Canavan disease. J Gene Med 2006;8:577–588.PubMedCrossRefGoogle Scholar
  10. 10.
    Mastakov MY, Baer K, Kotin RM, During MJ. Recombinant adeno-associated virus serotypes 2- and 5-mediated gene transfer in the mammalian brain: quantitative analysis of heparin co-infusion. Mol Ther 2002;5:371–380.PubMedCrossRefGoogle Scholar
  11. 11.
    Peel AL, Klein RL. Adeno-associated virus vectors: activity and applications in the CNS. J Neurosci Methods 2000;98:95–104.PubMedCrossRefGoogle Scholar
  12. 12.
    Coune PG, Schneider BL, Aebischer P. Parkinson’s disease: gene therapies. Cold Spring Harb Perspect Med 2012;2:a009431.PubMedCrossRefGoogle Scholar
  13. 13.
    Niidome T, Huang L. Gene therapy progress and prospects: nonviral vectors. Gene Ther 2002;9:1647–1652.PubMedCrossRefGoogle Scholar
  14. 14.
    Waszczak BL, Wachtman L, Newsome GC, et al. Intranasal GDNF for Parkinson’s disease: Next steps in preclinical development. FASEB J 2013;27:1177.10.Google Scholar
  15. 15.
    Lao CL, Kuo YH, Hsieh YT, Chen JC. Intranasal and subcutaneous administration of dopamine D3 receptor agonists functionally restores nigrostriatal dopamine in MPTP-treated mice. Neurotox Res 2013;24:523–531.PubMedCrossRefGoogle Scholar
  16. 16.
    Huwyler J, Wu D, Pardridge WM. Brain drug delivery of small molecules using immunoliposomes. Proc Natl Acad Sci U S A 1996;93:14164–14169.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Pardridge WM. Gene targeting in vivo with pegylated immunoliposomes. Methods Enzymol 2003;373:507–528.PubMedGoogle Scholar
  18. 18.
    Zhang Y, Calon F, Zhu C, Boado RJ, Pardridge WM. Intravenous nonviral gene therapy causes normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism. Human Gene Therapy 2003;14:1–12.PubMedCrossRefGoogle Scholar
  19. 19.
    Feng LR, Maguire-Zeiss KA. Gene therapy in Parkinson’s disease: rationale and current status. CNS Drugs 2010;24:177–192.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Levy R, Lang AE, Dostrovsky JO, et al. Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms. Brain 2001;124:2105–2118.PubMedCrossRefGoogle Scholar
  21. 21.
    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.PubMedCrossRefGoogle Scholar
  22. 22.
    Feigin A, Kaplitt MG, Tang C, et al. Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson’s disease. Proc Natl Acad Sci U S A 2007;104:19559–19564.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Feigin A, Eidelberg D. Gene transfer therapy for neurodegenerative disorders. Mov Disord 2007;22:1223–1228.PubMedCrossRefGoogle Scholar
  24. 24.
    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;10:309–319.PubMedCrossRefGoogle Scholar
  25. 25.
    Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-receptor treatment of Parkinson’s disease: scientific rationale and clinical implications. Lancet Neurol 2006;5:677–687.PubMedCrossRefGoogle Scholar
  26. 26.
    Eberling JL, Jagust WJ, Christine CW, et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 2008;70:1980–1983.PubMedCrossRefGoogle Scholar
  27. 27.
    Christine CW, Starr PA, Larson PS, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009;73:1662–1669.PubMedCrossRefGoogle Scholar
  28. 28.
    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;11:1509–1519.PubMedCrossRefGoogle Scholar
  29. 29.
    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;22:10302–10312.PubMedGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    OxfordBioMedica. Oxford BioMedica announces interim update on ProSavin® phase I/II study in Parkinson’s disease. Available at: Accessed July 12, 2013.
  32. 32.
    OxfordBioMedica. ProSavin®. Available at: Accessed July 12, 2013.
  33. 33.
    Berry AL, Foltynie T. Gene therapy: a viable therapeutic strategy for Parkinson’s disease? J Neurol 2011;258:179–188.PubMedCrossRefGoogle Scholar
  34. 34.
    Kearns CM, Gash DM. GDNF protects nigral dopamine neurons against 6-hydroxydopamine in vivo. Brain Res 1995;672:104–111.PubMedCrossRefGoogle Scholar
  35. 35.
    Sauer H, Rosenblad C, Björklund A. Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion. Proc Natl Acad Sci U S A 1995;92:8935–8939.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Grondin R, Cass WA, Zhang Z, Stanford JA, Gash DM, Gerhardt GA. Glial cell line-derived neurotrophic factor increases stimulus-evoked dopamine release and motor speed in aged rhesus monkeys. J Neurosci 2003;23:1974–1980.PubMedGoogle Scholar
  37. 37.
    Ai Y, Markesbery W, Zhang Z, et al. Intraputamenal infusion of GDNF in aged rhesus monkeys: distribution and dopaminergic effects. J Comp Neurol 2003;461:250–261.PubMedCrossRefGoogle Scholar
  38. 38.
    Grondin R, Zhang Z, Yi A, et al. Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys. Brain 2002;125:2191–2201.PubMedCrossRefGoogle Scholar
  39. 39.
    Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 2003;9:589–595.PubMedCrossRefGoogle Scholar
  40. 40.
    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.PubMedCrossRefGoogle Scholar
  41. 41.
    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;59:459–466.PubMedCrossRefGoogle Scholar
  42. 42.
    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;22:4942–4954.PubMedGoogle Scholar
  43. 43.
    Eslamboli A, Georgievska B, Ridley RM, et al. 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 2005;25:769–777.PubMedCrossRefGoogle Scholar
  44. 44.
    Eslamboli A, Cummings RM, Ridley RM, et al. Recombinant adeno-associated viral vector (rAAV) delivery of GDNF provides protection against 6-OHDA lesion in the common marmoset monkey (Callithrix jacchus). Exp Neurol 2003;184:536–548.PubMedCrossRefGoogle Scholar
  45. 45.
    Marks WJ, 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.PubMedCrossRefGoogle Scholar
  46. 46.
    Marks WJ, 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.PubMedCrossRefGoogle Scholar
  47. 47.
    Bartus RT, Baumann TL, Siffert J, et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 2013;80:1698–1701.PubMedCrossRefGoogle Scholar
  48. 48.
    Ceregene. Ceregene reports data from Parkinson’s disease phase 2b Study. Available at: Accessed July 12, 2013.
  49. 49. AAV2-GDNF for advanced Parkinson’s disease. Available at: Accessed July 12, 2013.
  50. 50.
    Kordower JH, Bjorklund A. Trophic factor gene therapy for Parkinson’s disease. Mov Disord 2013;28:96–109.PubMedCrossRefGoogle Scholar
  51. 51.
    Cederfjäll E, Nilsson N, Sahin G, et al. Continuous DOPA synthesis from a single AAV: dosing and efficacy in models of Parkinson’s disease. Sci Rep 2013;3:2157.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 2003;302:819–822.PubMedCrossRefGoogle Scholar
  53. 53.
    Lee VM, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 2006;52:33–38.PubMedCrossRefGoogle Scholar
  54. 54.
    Tofaris GK, Spillantini MG. Physiological and pathological properties of alpha-synuclein. Cell Mol Life Sci 2007;64:2194–2201.PubMedCrossRefGoogle Scholar
  55. 55.
    Maraganore DM, de Andrade M, Elbaz A, et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006;296:661–670.PubMedCrossRefGoogle Scholar
  56. 56.
    Mata IF, Shi M, Agarwal P, et al. SNCA variant associated with Parkinson disease and plasma alpha-synuclein level. Arch Neurol 2010;67:1350–1356.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Bellucci A, Navarria L, Falarti E, et al. Redistribution of DAT/α-synuclein complexes visualized by “in situ” proximity ligation assay in transgenic mice modelling early Parkinson’s disease. PLoS One 2011;6:e27959.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Fountaine TM, Wade-Martins R. RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport. J Neurosci Res 2007;85:351–363.PubMedCrossRefGoogle Scholar
  59. 59.
    Junn E, Lee KW, Jeong BS, Chan TW, Im JY, Mouradian MM. Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci U S A 2009;106:13052–13057.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Sapru MK, Yates JW, Hogan S, Jiang L, Halter J, Bohn MC. Silencing of human alpha-synuclein in vitro and in rat brain using lentiviral-mediated RNAi. Exp Neurol 2006;198:382–390.PubMedCrossRefGoogle Scholar
  61. 61.
    McCormack AL, Mak SK, Henderson JM, Bumcrot D, Farrer MJ, Di Monte DA. Alpha-synuclein suppression by targeted small interfering RNA in the primate substantia nigra. PLoS One 2010;5:e12122.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Khodr CE, Sapru MK, Pedapati J, et al. An α-synuclein AAV gene silencing vector ameliorates a behavioral deficit in a rat model of Parkinson’s disease, but displays toxicity in dopamine neurons. Brain Res 2011;1395:94–107.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Stefanis L. alpha-Synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med.2012;2:a009399.PubMedCrossRefGoogle Scholar
  64. 64.
    Markopoulou K, Ahlskog JE, Anderson K, et al. Genetic evidence for a dual and opposing effect of alpha-synuclein expression in preclinical versus clinical Parkinson’s disease (IN2-1.003). Neurology 2013;80(meeting abstracts 1):IN2-1.003.Google Scholar
  65. 65.
    Gorbatyuk OS, Li S, Nash K, et al. In vivo RNAi-mediated alpha-synuclein silencing induces nigrostriatal degeneration. Mol Ther 2010;18:1450–1457.PubMedCrossRefGoogle Scholar
  66. 66.
    Gorbatyuk OS, Li S, Nguyen FN, et al. α-Synuclein expression in rat substantia nigra suppresses phospholipase D2 toxicity and nigral neurodegeneration. Mol Ther 2010;18:1758–1768.PubMedCrossRefGoogle Scholar
  67. 67.
    Koo HJ, Choi MY, Im H. Aggregation-defective alpha-synuclein mutants inhibit the fibrillation of Parkinson’s disease-linked alpha-synuclein variants. Biochem Biophys Res Commun 2009;386:165–169.PubMedCrossRefGoogle Scholar
  68. 68.
    Lücking CB, Dürr A, Bonifati V, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 2000;342:1560–1567.PubMedCrossRefGoogle Scholar
  69. 69.
    Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 2000;25:302–305.PubMedCrossRefGoogle Scholar
  70. 70.
    Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008;183:795–803.PubMedCrossRefGoogle Scholar
  71. 71.
    Vercammen L, Van der Perren A, Vaudano E, et al. Parkin protects against neurotoxicity in the 6-hydroxydopamine rat model for Parkinson’s disease. Mol Ther 2006;14:716–723.PubMedCrossRefGoogle Scholar
  72. 72.
    Paterna JC, Leng A, Weber E, Feldon J, Büeler H. DJ-1 and Parkin modulate dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron loss in mice. Mol Ther 2007;15:698–704.PubMedCrossRefGoogle Scholar
  73. 73.
    Lo Bianco C, Schneider BL, Bauer M, et al. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an alpha-synuclein rat model of Parkinson’s disease. Proc Natl Acad Sci U S A 2004;101:17510–17515.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Yamada M, Mizuno Y, Mochizuki H. Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson’s disease. Hum Gene Ther 2005;16:262–270.PubMedCrossRefGoogle Scholar
  75. 75.
    Yasuda T, Miyachi S, Kitagawa R, et al. Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates. Neuroscience 2007;144:743–753.PubMedCrossRefGoogle Scholar
  76. 76.
    de Yñigo-Mojado L, Martín-Ruíz I, Sutherland JD. Efficient allele-specific targeting of LRRK2 R1441 mutations mediated by RNAi. PLoS One 2011;6:e21352.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Keeney PM, Quigley CK, Dunham LD, et al. Mitochondrial gene therapy augments mitochondrial physiology in a Parkinson’s disease cell model. Hum Gene Ther 2009;20:897–907.PubMedCrossRefGoogle Scholar
  78. 78.
    Marella M, Seo BB, Yagi T, Matsuno-Yagi A. Parkinson’s disease and mitochondrial complex I: a perspective on the Ndi1 therapy. J Bioenerg Biomembr 2009;41:493–497.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Barber-Singh J, Seo BB, Nakamaru-Ogiso E, Lau YS, Matsuno-Yagi A, Yagi T. Neuroprotective effect of long-term NDI1 gene expression in a chronic mouse model of Parkinson disorder. Rejuvenation Res 2009;12:259–267.PubMedCrossRefGoogle Scholar
  80. 80.
    McCoy MK, Ruhn KA, Martinez TN, McAlpine FE, Blesch A, Tansey MG. Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol Ther 2008;16:1572–1579.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Harms AS, Barnum CJ, Ruhn KA, et al. Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson’s disease. Mol Ther 2011;19:46–52.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2013

Authors and Affiliations

  1. 1.Center for NeurosciencesThe Feinstein Institute for Medical ResearchManhassetUSA

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