, Volume 16, Issue 1, pp 166–175 | Cite as

Gene Therapy for Neurodegenerative Diseases

  • Vivek Sudhakar
  • R. Mark RichardsonEmail author


Gene therapy has the potential to provide therapeutic benefit to millions of people with neurodegenerative diseases through several means, including direct correction of pathogenic mechanisms, neuroprotection, neurorestoration, and symptom control. Therapeutic efficacy is therefore dependent on knowledge of the disease pathogenesis and the required temporal and spatial specificity of gene expression. An additional critical challenge is achieving the most complete transduction of the target structure while avoiding leakage into neighboring regions or perivascular spaces. The gene therapy field has recently entered a new technological era, in which interventional MRI-guided convection-enhanced delivery (iMRI-CED) is the gold standard for verifying accurate vector delivery in real time. The availability of this advanced neurosurgical technique may accelerate the translation of the promising preclinical therapeutics under development for neurodegenerative disorders, including Parkinson’s, Huntington’s, and Alzheimer’s diseases.

Key Words

Gene therapy Parkinson’s disease Huntington’s disease Alzheimer’s disease viral vector intraoperative MRI. 


Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2018_694_MOESM1_ESM.pdf (498 kb)
ESM 1 (PDF 498 kb)


  1. 1.
    Richardson RM, Varenika V, Forsayeth JR, Bankiewicz KS (2009) Future applications: gene therapy. Neurosurg Clin N Am 20:205–210CrossRefGoogle Scholar
  2. 2.
    Palfi S, Gurruchaga JM, Ralph GS, et al (2014) Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet 383:1138–1146CrossRefGoogle Scholar
  3. 3.
    Salegio EA, Samaranch L, Kells AP, et al (2013) Axonal transport of adeno-associated viral vectors is serotype-dependent. Gene Therapy 20:348–352CrossRefGoogle Scholar
  4. 4.
    Ciesielska A, Mittermeyer G, Hadaczek P, Kells AP, Forsayeth J, Bankiewicz KS (2011) Anterograde Axonal Transport of AAV2-GDNF in Rat Basal Ganglia. Mol Ther 19:922–927CrossRefGoogle Scholar
  5. 5.
    Samaranch L, Blits B, San Sebastian W, et al (2017) MR-guided parenchymal delivery of adeno-associated viral vector serotype 5 in non-human primate brain. Gene Ther doi:
  6. 6.
    Green F, Samaranch L, Zhang HS, et al (2016) Axonal transport of AAV9 in nonhuman primate brain. Gene Ther 23:520–526CrossRefGoogle Scholar
  7. 7.
    San Sebastian W, Samaranch L, Heller G, et al (2013) Adeno-associated virus type 6 is retrogradely transported in the non-human primate brain. Gene Ther 20:1178–1183CrossRefGoogle Scholar
  8. 8.
    Samaranch L, Salegio EA, San Sebastian W, et al (2013) Strong cortical and spinal cord transduction after AAV7 and AAV9 delivery into the cerebrospinal fluid of nonhuman primates. Hum Gene Ther 24:526–532CrossRefGoogle Scholar
  9. 9.
    Kells AP, Hadaczek P, Yin D, et al (2009) Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. PNAS 106:2407–2411CrossRefGoogle Scholar
  10. 10.
    Eberling JL, Jagust WJ, Christine CW, et al (2008) Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 70:1980–1983CrossRefGoogle Scholar
  11. 11.
    Marks WJ, Ostrem JL, Verhagen L, et al (2008) 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 7:400–408CrossRefGoogle Scholar
  12. 12.
    Christine CW, Starr PA, Larson PS, et al (2009) Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 73:1662–1669CrossRefGoogle Scholar
  13. 13.
    Muramatsu S, Fujimoto K, Kato S, et al (2010) A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol Ther 18:1731–1735CrossRefGoogle Scholar
  14. 14.
    Rafii MS, Tuszynski MH, Thomas RG, et al (2018) Adeno-Associated Viral Vector (Serotype 2)-Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol 75:834–841CrossRefGoogle Scholar
  15. 15.
    Marks WJ, Bartus RT, Siffert J, et al (2010) Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 9:1164–1172CrossRefGoogle Scholar
  16. 16.
    LeWitt PA, Rezai AR, Leehey MA, et al (2011) AAV2-GAD gene therapy for advanced Parkinson’s disease: A double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 10:309–319CrossRefGoogle Scholar
  17. 17.
    Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 91:2076–2080CrossRefGoogle Scholar
  18. 18.
    Krauze MT, Saito R, Noble C, et al (2005) Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 103:923–929CrossRefGoogle Scholar
  19. 19.
    Varenika V, Dickinson P, Bringas J, et al (2008) Detection of infusate leakage in the brain using real-time imaging of convection-enhanced delivery. J Neurosurg 109:874–880CrossRefGoogle Scholar
  20. 20.
    Varenika V, Kells AP, Valles F, Hadaczek P, Forsayeth J, Bankiewicz KS (2009) Controlled dissemination of AAV vectors in the primate brain. Prog Brain Res 175:163–172CrossRefGoogle Scholar
  21. 21.
    Valles F, Fiandaca MS, Bringas J, et al (2009) Anatomic compression caused by high-volume convection-enhanced delivery to the brain. Neurosurgery 65:579–585; discussion 585-586CrossRefGoogle Scholar
  22. 22.
    Valles F, Fiandaca MS, Eberling JL, et al (2010) Qualitative imaging of adeno-associated virus serotype 2-human aromatic L-amino acid decarboxylase gene therapy in a phase i study for the treatment of parkinson disease. Neurosurgery 67:1377–1385CrossRefGoogle Scholar
  23. 23.
    Yin D, Richardson RM, Fiandaca MS, et al (2010) Cannula placement for effective convection-enhanced delivery in the nonhuman primate thalamus and brainstem: implications for clinical delivery of therapeutics. J Neurosurg 113:240–248CrossRefGoogle Scholar
  24. 24.
    Yin D, Valles FE, Fiandaca MS, 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:S196–203CrossRefGoogle Scholar
  25. 25.
    Richardson RM, Kells AP, Martin AJ, et al (2011) Novel platform for MRI-guided convection-enhanced delivery of therapeutics: Preclinical validation in nonhuman primate brain. Stereotact Funct Neurosurg 89:141–151CrossRefGoogle Scholar
  26. 26.
    Su X, Kells AP, Salegio EA, et al (2010) Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther 18:1490–1495CrossRefGoogle Scholar
  27. 27.
    Richardson RM, Kells AP, Rosenbluth KH, et al (2011) Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson’s disease. Mol Ther 19:1048–1057CrossRefGoogle Scholar
  28. 28.
    Larson PS, Starr PA, Bates G, Tansey L, Richardson RM, Martin AJ (2012) An optimized system for interventional magnetic resonance imaging-guided stereotactic surgery: preliminary evaluation of targeting accuracy. Neurosurgery 70:95–103; discussion 103CrossRefGoogle Scholar
  29. 29.
    Ostrem JL, Ziman N, Galifianakis NB, et al (2016) Clinical outcomes using ClearPoint interventional MRI for deep brain stimulation lead placement in Parkinson’s disease. J Neurosurg 124:908–916CrossRefGoogle Scholar
  30. 30.
    Sidiropoulos C, Rammo R, Merker B, et al (2016) Intraoperative MRI for deep brain stimulation lead placement in Parkinson’s disease: 1 year motor and neuropsychological outcomes. J Neurol 263:1226–1231CrossRefGoogle Scholar
  31. 31.
    Lee PS, Weiner GM, Corson D, et al (2018) Outcomes of Interventional-MRI Versus Microelectrode Recording-Guided Subthalamic Deep Brain Stimulation. Front Neurol doi:
  32. 32.
    Levy R, Lang AE, Dostrovsky JO, et al (2001) Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms. Brain 124:2105–2118CrossRefGoogle Scholar
  33. 33.
    Emborg ME, Carbon M, Holden JE, et al (2007) Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism. J Cereb Blood Flow Metab 27:501–509CrossRefGoogle Scholar
  34. 34.
    Kaplitt MG, Feigin A, Tang C, et al (2007) 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 369:2097–2105CrossRefGoogle Scholar
  35. 35.
    Bankiewicz KS, Forsayeth J, Eberling JL, et al (2006) Long-Term Clinical Improvement in MPTP-Lesioned Primates after Gene Therapy with AAV-hAADC. Mol Ther 14:564–570CrossRefGoogle Scholar
  36. 36.
    Hadaczek P, Eberling JL, Pivirotto P, Bringas J, Forsayeth J, Bankiewicz KS (2010) Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol Ther 18:1458–61CrossRefGoogle Scholar
  37. 37.
    Forsayeth JR, Eberling JL, Sanftner LM, et al (2006) A Dose-Ranging Study of AAV-hAADC Therapy in Parkinsonian Monkeys. Mol Ther 14:571–577CrossRefGoogle Scholar
  38. 38.
    San Sebastian W, Richardson RM, Kells AP, et al (2012) Safety and tolerability of magnetic resonance imaging-guided convection-enhanced delivery of AAV2-hAADC with a novel delivery platform in nonhuman primate striatum. Hum Gene Ther 23:210–217CrossRefGoogle Scholar
  39. 39.
    Bankiewicz KS, Eberling JL, Kohutnicka M, 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 164:2–14CrossRefGoogle Scholar
  40. 40.
    Mittermeyer G, Christine CW, Rosenbluth KH, et al (2012) Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson’s disease. Hum Gene Ther 23:377–381CrossRefGoogle Scholar
  41. 41.
    Dass B, Olanow CW, Kordower JH (2006) Gene transfer of trophic factors and stem cell grafting as treatments for Parkinson’s disease. Neurology 66:S89–S103CrossRefGoogle Scholar
  42. 42.
    Lang AE, Gill S, Patel NK, et al (2006) Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 59:459–466CrossRefGoogle Scholar
  43. 43.
    Gill SS, Patel NK, Hotton GR, et al (2003) Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 9:589–595CrossRefGoogle Scholar
  44. 44.
    Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B (2005) Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line—derived neurotrophic factor. J Neurosurg 102:216–222CrossRefGoogle Scholar
  45. 45.
    Salvatore MF, Ai Y, Fischer B, et al (2006) Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol 202:497–505CrossRefGoogle Scholar
  46. 46.
    Barua N, Gill S (2018) Drug Delivery for Movement Disorders. Curr Concepts Mov Disord Manag 33:243–252CrossRefGoogle Scholar
  47. 47.
    Kordower JH, Emborg ME, Bloch J, et al (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290:767–73CrossRefGoogle Scholar
  48. 48.
    Johnston LC, Eberling J, Pivirotto P, et al (2009) Clinically Relevant Effects of Convection-Enhanced Delivery of AAV2-GDNF on the Dopaminergic Nigrostriatal Pathway in Aged Rhesus Monkeys. Hum Gene Ther 20:497–510CrossRefGoogle Scholar
  49. 49.
    Su X, Kells AP, Huang EJ, et al (2009) Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Hum Gene Ther 20:1627–1640CrossRefGoogle Scholar
  50. 50.
    Kells AP, Eberling J, Su X, et al (2010) Regeneration of the MPTP-Lesioned Dopaminergic System after Convection-Enhanced Delivery of AAV2-GDNF. J Neurosci 30:9567–9577CrossRefGoogle Scholar
  51. 51.
    Cik M, Masure S, Lesage ASJ, et al (2000) Binding of GDNF and Neurturin to Human GDNF family receptor alpha 1 and 2: Influence of cRET and cooperative interactions. J Biol Chem 275:27505–27512Google Scholar
  52. 52.
    Kordower JH, Herzog CD, Dass B, 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 60:706–715CrossRefGoogle Scholar
  53. 53.
    Olanow WC, Bartus RT, Baumann TL, et al (2015) Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial. Ann Neurol 78:248–257CrossRefGoogle Scholar
  54. 54.
    Bartus RT, Baumann TL, Siffert J, et al (2013) Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 80:1698–1701CrossRefGoogle Scholar
  55. 55.
    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 72:971–983CrossRefGoogle Scholar
  56. 56.
    Ross CA, Tabrizi SJ (2011) Huntington’s disease: From molecular pathogenesis to clinical treatment. Lancet Neurol 10:83–98CrossRefGoogle Scholar
  57. 57.
    Saudou F, Humbert S (2016) The Biology of Huntingtin. Neuron 89:910–926CrossRefGoogle Scholar
  58. 58.
    Yamamoto A, Lucas JJ, Hen R (2000) Reversal of Neuropathology and Motor Dysfunction in a Conditional Model of Huntington’s Disease. Cell 101:57–66CrossRefGoogle Scholar
  59. 59.
    Hutvagner G, Simard MJ (2008) Argonaute proteins: Key players in RNA silencing. Nat Rev Mol Cell Biol 9:22–32CrossRefGoogle Scholar
  60. 60.
    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 19:2152–2162CrossRefGoogle Scholar
  61. 61.
    Grondin R, Kaytor MD, Ai Y, et al (2012) Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 135:1197–1209CrossRefGoogle Scholar
  62. 62.
    Miniarikova J, Zanella I, Huseinovic A, et al (2016) Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington’s Disease. Mol Ther Nucleic Acids 5:e297CrossRefGoogle Scholar
  63. 63.
    Miniarikova J, Zimmer V, Martier R, et al (2017) AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington’s disease. Gene Ther 24:630–639CrossRefGoogle Scholar
  64. 64.
    Evers MM, Miniarikova J, Juhas S, et al (2018) AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington’s Disease Minipig Model. Mol Ther 26:2163–2177CrossRefGoogle Scholar
  65. 65.
    Koliatsos VE, Nauta HJ, Clatterbuck RE, Holtzman DM, Mobley WC, Price DL (1990) Mouse nerve growth factor prevents degeneration of axotomized basal forebrain cholinergic neurons in the monkey. J Neurosci 10:3801–3813CrossRefGoogle Scholar
  66. 66.
    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 91:10898–10902CrossRefGoogle Scholar
  67. 67.
    Tuszynski MH, Roberts J, Senut MC, U HS, Gage FH (1996) Gene therapy in the adult primate brain: intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. Gene Ther 3:305–314Google Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  1. 1.Brain Modulation Laboratory, Department of Neurological SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations