Somatic gene therapy in animal models of Parkinson’s disease

  • M. Bauer
  • M. Ueffing
  • T. Meitinger
  • T. Gasser
Conference paper
Part of the 6th International Winter Conference on N eurodegeneration book series (NEURAL SUPPL, volume 55)


Gene therapy in Parkinson’s disease (PD) emerged about 10 years ago but until now, no clinical trials are under way, because most approaches have failed to show long-term therapeutic effects in PD animal models and because safety concerns precluded the use in humans so far. This review tries to give an overview on the development of different strategies in gene therapy in PD animal models and point out new and possibly more successful directions, including the transplantation of neural precursor cells and pig tissue.


Gene Therapy Tyrosine Hydroxylase Primary Fibroblast Gene Therapy Approach Nondividing Cell 
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  1. Afione SA, Conrad CK, Kearns WG, Chunduru S, Adams R, Reynolds TC, Guggino WB, Cutting GR, Carter BJ, Flotte TR (1996) In vivo model of adeno-associated virus vector persistence and rescue. J Virol 70: 3235–3241.PubMedGoogle Scholar
  2. Akli S, Caillaud C, Vigne E, Startford-Perricaudet LD, Poenaru L, Perricaudet M, Kahn A, Peschanski MR (1993) Transfer of foreign gene into the brain using adenovirus vectors. Nat Gen 3: 224–228.CrossRefGoogle Scholar
  3. Anderson WF (1998) Human gene therapy. Nature 392: S25–S30.CrossRefGoogle Scholar
  4. Anton R, Kordower JH, Maidment NT, Manaster JS, Kane DJ, Rabizadeh S, Schueller SB, Yang J, Edwards RH, Markham CH, Bredesen DE (1994) Neural-targeted gene therapy for rodent and primate hemiparkinsonism. Exp Neurol 127: 207–218.PubMedCrossRefGoogle Scholar
  5. Bencsics C, Wachtel RS, Milstien S, Kang UJ (1996) Double transduction with GTP cyclohydrolase 1 and tyrosine hydroxylase is necessary for spontaneous synthesis of L-dopa by primary fibroblasts. J Neurosci 16: 4449–4456.PubMedGoogle Scholar
  6. Berns KI, Bohenzky RA (1987) Adeno-associated viruses: an update. Adv Virus Res 32:243–306.PubMedCrossRefGoogle Scholar
  7. Bilang-Bleuel A, Revah F, Colin P, Locquet I, Robert JJ, Mallet J, Horellou P (1997) Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioural impairment in a rat model of Parkinson disease. Proc Natl Acad Sci USA 94: 8818–8823.PubMedCrossRefGoogle Scholar
  8. Björklund A, Rosenblad C, Winkler C, Kirik D (1997) Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson’s disease. Neurobiol Dis 4: 186–200.PubMedCrossRefGoogle Scholar
  9. Buc-Caron MH (1995) Neuroepithelial progenitor cells explanted from human fetal brain proliferate and differentiate in vitro. Neurobiol Dis 2: 37–47.PubMedCrossRefGoogle Scholar
  10. Bukrinsky MI, Haggerty S, Dempsey MP, Sharova N, Adzhubei A, Spitz L, Lewis P, Goldfarb D, Emerman M, Stevenson M (1993) A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature 365: 666–669.PubMedCrossRefGoogle Scholar
  11. Choi-Lundberg D, Lin Q, Chang Y, Chiang YL, Hay CM, Mohajeri H, Davidson BL, Bohn MC (1997) Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275: 838–841.PubMedCrossRefGoogle Scholar
  12. Cunningham LA, Hansen JT, Short MP, Bohn MC (1991) The use of genetically altered astrocytes to provide nerve growth factor to adrenal chromaffin cells grafted into the striatum. Brain Res 561: 192–202.PubMedCrossRefGoogle Scholar
  13. Deacon T, Schumacher J, Dinsmore J, Thomas C, Palmer P, Isacson O (1997) Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson’s disease. Nat Med 3: 350–353.PubMedCrossRefGoogle Scholar
  14. Dorling A, Riesbeck K, Warrens A, Lechler R (1997) Clinical xenotransplantation of solid organs. Lancet 349: 867–871.PubMedCrossRefGoogle Scholar
  15. Dörig RE, Marcil A, Chopra A, Richardson CD (1993) The human CD46 molecule is a receptor for measles virus (Edmonston Strain). Cell 75: 295–305.PubMedCrossRefGoogle Scholar
  16. During MJ, Naegele JR, O’Malley KL, Geller AI (1994) Long-term behavioral recovery in parkinsonian rats by an HSV vector expressing tyrosine hydroxylase. Science 266: 1399–1403.PubMedCrossRefGoogle Scholar
  17. During MJ, Samulski RJ, Elsworth JD, Kaplitt MG, Leone P, Xiao X, Li J, Freese A (1998) In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vector. Gene Ther 5: 820–827.PubMedCrossRefGoogle Scholar
  18. Duvoisin R (1992) Overview of Parkinson’s disease. Ann N Y Acad Sci 648: 187–193.PubMedCrossRefGoogle Scholar
  19. Fearnley JM, Lees AJ (1991) Aging and Parkinson’s disease: Substantia nigra regional specificity. Brain 114: 2283–2301.PubMedCrossRefGoogle Scholar
  20. Ferrari FK, Samulski T, Shenk T, Samulski RJ (1996) Second-strand synthesis is a ratelimiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol 70: 3227–3234.PubMedGoogle Scholar
  21. Fink DJ, Sternberg PC, Weber M, Mata M, Goins WF, Glorioso JC (1992) In vivo expression of beta-galactosidase in hippocampal neurons by HSV-mediated gene transfer. Hum Gene Ther 3: 11–19.PubMedCrossRefGoogle Scholar
  22. Fisher L, Jinnah H, Kale L, Higgins G, Gage F (1991) Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce L-DOPA. Neuron 6: 371–380.PubMedCrossRefGoogle Scholar
  23. Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropath Exp Neurol 55: 259–272.PubMedCrossRefGoogle Scholar
  24. Frederiksen K, Jat PS, Valtz N, Levy D, McKay R (1988) Immortalization of precursor cells from the mammalian CNS. Neuron 1: 439–448.PubMedCrossRefGoogle Scholar
  25. Freed CR, Breeze RE, Rosenberg NL, Schneck SA, Kriek E, Qi JX, Lone T, Zhang YB, Snyder JA, Wells TH, et al (1992) Survival of implanted fetal dopamine cells and neurological improvement 12 to 46 months after transplantation for Parkinson’s disease. N Engl J Med 327: 1549–1555.PubMedCrossRefGoogle Scholar
  26. Freese A, Stern M, Kaplitt MG, O’Connor WM, Abbey MV, O’Connor MJ, During MJ (1996) Prospects for gene therapy in Parkinson’s disease. Mov Disord 11: 469–488.PubMedCrossRefGoogle Scholar
  27. Frim DM, Uhler TA, Galpern WR, Beal MF, Breakfield XO, Isacson O (1994) Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent MPTP toxicity to dopaminergic neurons in the rat. Proc Natl Acad Sci USA 91: 5104–5108.PubMedCrossRefGoogle Scholar
  28. Gage F (1998) Cell therapy. Nature 392: S18–S24.Google Scholar
  29. Gage F, Coates PW, Palmer TD, Kuhn HG, Fisher L, Suhonen JO, Peterson DA, Suhr ST, Ray J (1995) Survival and differentation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA 92: 11879–11883.PubMedCrossRefGoogle Scholar
  30. Geller AI, Freese A (1990) Infection of cultured central nervous system neurons with a defective herpes simplex virus 1 vector results in stable expression of E. coli betagalactosidase. Proc Natl Acad Sci USA 87: 1149–1153.PubMedCrossRefGoogle Scholar
  31. Geller AI, Freese A, During MJ, O’Malley KL (1995) A HSV-1 vector expressing tyrosine hydroxylase causes production and release of L-dopa from cultured rat striatal cells. J Neurochem 64: 487–496.PubMedCrossRefGoogle Scholar
  32. Giulian D, Lachman LB (1985) Interleukin-1 stimulation of astroglial proliferation after brain injury. Science 228: 497–499.PubMedCrossRefGoogle Scholar
  33. Glorioso JC, Goins WF, Meaney CA, Fink DJ, DeLuca NA (1994) Gene transfer to brain using herpes simplex virus vectors. Ann Neurol 35: S28–S34.PubMedCrossRefGoogle Scholar
  34. Graham FL, Smiley J, Russell WC, Nairn R (1977) Characteristics of a human cell line transformed by DNA from human adenovirus 5. J Gen Virol 36: 59–72.PubMedCrossRefGoogle Scholar
  35. Hagg T, Varon S (1993) Ciliary neurotrophic factor prevents degeneration of adult rat substantia nigra dopaminergic neurons in vivo. Proc Natl Acad Sci USA 90: 6315–6319.PubMedCrossRefGoogle Scholar
  36. Heckl-Ostreicher B, Binder R, Kirschfink M (1995) Functional activity of the membranassociated complement inhibitor CD59 in a pig to human in vitro model for hyperacute xenograft rejection. Clin Exp Immunol 102: 589–595.PubMedCrossRefGoogle Scholar
  37. Hefti F, Hartikka J, Schlumpf M (1985) Implantation of PC12 cells into the corpus striatum of rats with lesions of the dopaminergic nigrostriatal neurons. Brain Res 348: 283–288.PubMedCrossRefGoogle Scholar
  38. Horellou P, Guibert B (1989) Retroviral transfer of a human tyrosine hydroxylase cDNA in various cell lines: regulated release of dopamine in mouse anterior pituitary AtT-20 cells. Proc Natl Acad Sci USA 86: 7233–7237.PubMedCrossRefGoogle Scholar
  39. Horellou P, Brundin P, Kalen P, Mallet J, Björklund A (1990a) In vivo release of DOPA and dopamine from genetically engineered cells grafted to the denervated rat striatum. Neuron 5: 393–402.PubMedCrossRefGoogle Scholar
  40. Horellou P, Marlier L, Privat A, Mallet J (1990b) Behavioural effect of engineered cells that synthesize L-DOPA or dopamine after grafting into the rat neostriatum. Eur J Neurosci 2: 116–119.PubMedCrossRefGoogle Scholar
  41. Horellou P, Marlier L, Privat A, Mallet J (1990c) Exogenous expression of L-dopa and dopamine in various cell lines following transfer of rat and human tyrosine hydroxylase cDNA: Grafting in an animal model of Parkinson’s disease. Prog Brain Res 82: 23–32.PubMedCrossRefGoogle Scholar
  42. Horellou P, Vigne E, Castel MN, Barneoud P, Colin P, Perricaudet M, Delaere P, Mallet J (1994) Direct intracerebral gene transfer of an adenoviral vector expressing tyrosine hydroxylase in a rat model of Parkinson’s disease. Neuroreport 6: 49–53.PubMedCrossRefGoogle Scholar
  43. Horellou P, Sabate O, Buc-Caron MH, Mallet J (1997) Adenovirus-mediated gene transfer to the central nervous system for Parkinson’s disease. Exp Neurol 144: 131–138.PubMedCrossRefGoogle Scholar
  44. Hulspas R, Tiarks C, Reilly J, Hsieh CC, Recht L, Quesenberry PJ (1997) In vitro cell density-dependent clonal growth of EGF-responsive murine neural progenitor cells under serum-free conditions. Exp Neurol 148:147–156.PubMedCrossRefGoogle Scholar
  45. Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP, Lindsay RM (1991) BDNF is an neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350: 230–232.PubMedCrossRefGoogle Scholar
  46. Hyman C, Juhasz C, Jackson C, Wright P, Ip NY, Lindsay RM (1994) Overlapping and distinct actions of the neurotrophins BDNF, NT-3 and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. J Neurosci 14: 335–347.PubMedGoogle Scholar
  47. Jiao S, Schultz E, Wolff J (1992a) Intracerebral transplants of primary muscle cells: A potential “platform” for transgene expression in the brain. Brain Res 575:143–147.PubMedCrossRefGoogle Scholar
  48. Jiao S, Wolff J (1992b) Long-term survival of autologous muscle grafts in rat brain. Neurosci Lett 137: 207–210.PubMedCrossRefGoogle Scholar
  49. Jiao S, Gurevich V, Wolff J (1993) Long-term correction of rat model of Parkinson’s disease by gene therapy. Nature 362: 450–453.PubMedCrossRefGoogle Scholar
  50. Kaplitt MG, Leone P, Samulski RJ, Xiao X, Pfaff DW, O’Malley KL, During MJ (1994) Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Gen 8: 148–154.CrossRefGoogle Scholar
  51. Karpati G, Lochmüller H, Nalbantoglu J, Durham H (1996) The principles of gene therapy for the nervous system. Trends Neurosci 19: 49–54.PubMedCrossRefGoogle Scholar
  52. Kawaja M, Gage F (1992) Morphological and neurochemical features of cultured primary skin fibroblasts of Fischer 344 rats following striatal implantation. J Comp Neurol 317: 102–116.PubMedCrossRefGoogle Scholar
  53. Kawaja M, Fagan AM, Firestein BL, Gage F (1991) Intracerebral grafting of cultured autologous skin fibroblasts into rat striatum: An assessment of graft size and ultrastructure. J Comp Neurol 307: 695–706.PubMedCrossRefGoogle Scholar
  54. Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94: 507–522.PubMedCrossRefGoogle Scholar
  55. Kim VN, Mitrophanous K, Kingsman SM, Kingsman AJ (1998) Minimal requirement for a lentivirus vector based on human immundeficiency virus type 1. J Virol 72: 811–816.PubMedGoogle Scholar
  56. Kordower JH, Goetz CG, Freeman TB, Olanow CW (1997) Dopaminergic transplants in patients with Parkinson’s disease: Neuroanatomical correlates of clinical recovery. Exp Neurol 144: 41–46.PubMedCrossRefGoogle Scholar
  57. Lange K, Youdim M, Riederer P (1992) Neurotoxicity and neuroprotection in Parkinson’s disease. J Neural Transm 38: 27–44.Google Scholar
  58. Le Gal La Salle G, Robert JJ, Berrard S, Ridoux V, Startford-Perricaudet LD, Perricaudet M, Mallet J (1993) An adenovirus vector for gene transfer into neurons and glia in the brain. Science 259: 988–990.PubMedCrossRefGoogle Scholar
  59. Levine RA, Miller LP, Lovenberg W (1981) Tetrahydrobiopterin in striatum: localization in dopamine nerve terminals and role in catecholamine synthesis. Science 213: 349–350.CrossRefGoogle Scholar
  60. Levivier M, Przedborski S, Bencsics C, Kang UJ (1995) Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in rat model of Parkinson’s disease. J Neurosci 15: 7810–7820.PubMedGoogle Scholar
  61. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260: 1130–1132.PubMedCrossRefGoogle Scholar
  62. Lundberg C, Horellou P, Mallet J, Björklund A (1996) Generation of dopa-producing astrocytes by retro viral transduction of the human tyrosine hydroxylase gene: in vitro characterization and in vivo effects in the rat Parkinson model. Exp Neurol 139: 39–53.PubMedCrossRefGoogle Scholar
  63. Mayer E, Dunnett SB, Fawcett JW (1993) Mitogenic effect of basic fibroblast growth factor on embryonic ventral mesencephalic dopaminergic neuron precursors. Brain Res Dev Brain Res 72: 253–258.PubMedCrossRefGoogle Scholar
  64. Mehler MF, Rozental R, Dougherty M, Spray DC, Kessler JA (1993) Cytokine regulation of neural differentiation of hippocampal progenitor cells. Science 362: 62–65.Google Scholar
  65. Meignier B, Longnecker R, Mavromara-Nazos P, Sears A, Roizman B (1988) Virulence of and establishment of latency by genetically engineered deletion mutants of herpes simplex virus type 1. Virology 162: 251–254.PubMedCrossRefGoogle Scholar
  66. Mytilineou C, Park TH, Shen J (1992) Epidermal growth factor-induced survival and proliferation of neuronal precursor cells from embryonic rat mesencephalon. Neurosci Lett 135: 62–66.PubMedCrossRefGoogle Scholar
  67. Naldini L, Blomer U, Gage F, Trono D, Verma IM (1996a) Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA 93: 11382–11388.PubMedCrossRefGoogle Scholar
  68. Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage F, Verma IM, Trono D (1996b) In vivo gene delivery and stable transduction of nondividing cells by lentiviral vector. Science 272: 263–267.PubMedCrossRefGoogle Scholar
  69. Onifer S, Whittemore SR, Holets VR (1993) Variable morphological differentation of a rapid-derived neuronal cell line following transplantation into the adult rat CNS. Exp Neurol 122:130–142.PubMedCrossRefGoogle Scholar
  70. Partridge TA, Davies KE (1995) Myoblast-based gene therapies. Br Med Bull 51:123–137.PubMedGoogle Scholar
  71. Patience C, Takeuchi Y, Weiss RA (1997) Infection of human cells by an endogenous retrovirus of pigs. Nat Med 3: 282–286.PubMedCrossRefGoogle Scholar
  72. Platt JL (1994) A perspective on xenograft rejection and accommodation. Immunol Rev 141: 127–149.PubMedCrossRefGoogle Scholar
  73. Platt JL (1998) New directions for organ transplantation. Nature 392: S11–S17.CrossRefGoogle Scholar
  74. Ramakrishnan R, Fink DJ, Guihua J, Desai P, Glorioso JC, Levine M (1994) Competitive quantitative Polymerase chain reaction (PCR) analysis of herpes simplex virus typ 1 DNA and LAT RNA in latently infected cells of the rat brain. J Virol 68: 1864–1870.PubMedGoogle Scholar
  75. Raymon HK, Thode S, Gage F (1997) Application of ex vivo gene therapy in the treatment of Parkinson’s disease. Exp Neurol 144: 82–91.PubMedCrossRefGoogle Scholar
  76. Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255: 1707–1710.PubMedCrossRefGoogle Scholar
  77. Reynolds BA, Weiss RA (1996) Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 175: 1–13.PubMedCrossRefGoogle Scholar
  78. Richards LJ, Kilpatrick TJ, Bartlett PF (1992) De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci USA 89: 8591–8595.PubMedCrossRefGoogle Scholar
  79. Rother RP, Fodor WL, Springhorn JP, Birks CW, Setter E, Sandrin MS, Squinto SP, Rollins SA (1995) A novel mechanism of retrovirus inactivation in human serum mediated by anti-alpha galactosyl natural antibody. J Exp Med 182: 1345–1355.PubMedCrossRefGoogle Scholar
  80. Sabate O, Horellou P, Vigne E, Colin P, Perricaudet M, Buc-Caron MH, Mallet J (1995) Transplantation to the rat brain of human neural progenitors that were genetically modified using adenoviruses. Nat Gen 9: 256–260.CrossRefGoogle Scholar
  81. Sachs DH, Bach FH (1990) Immunology of xenograft rejection. Hum Immunol 28: 245–251.PubMedCrossRefGoogle Scholar
  82. Samulski JS, Chang LS, Shenk T (1989) Helper-free stocks of adeno-associated viruses: normal integration does not require viral gene expression. J Virol 63: 3822–3828.PubMedGoogle Scholar
  83. Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59: 401–415.PubMedCrossRefGoogle Scholar
  84. Sautter J, Tseng JL, Braguglia D, Aebischer P, Spenger C, Seiler RW, Widmer HR, Zurn AD (1998) Implants of polymer-encapsulated genetically modified cells releasing glial cell line-derived neurotrophic factor improve survival, growth and function of dopaminergic grafts. Exp Neurol 149: 230–236.PubMedCrossRefGoogle Scholar
  85. Shetty AK, Turner DA (1998) In vitro survival and differentation of neurons derived from epidermal growth factor-responsive postnatal hippocampal stem cells: inducing effects of brain-derived neurotrophic factor. J Neurobiol 35: 395–425.PubMedCrossRefGoogle Scholar
  86. Snyder EY, Deitcher DL, Walsh C, Arnold-Aldea S, Hartwieg EA, Cepko CL (1992) Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68: 33–51.PubMedCrossRefGoogle Scholar
  87. Spaete R, Frenkel N (1982) The herpes simplex virus amplicon: A new eucaryotic defective-virus cloning amplifying vector. Cell 30: 295–304.PubMedCrossRefGoogle Scholar
  88. Speck PG, Simmons A (1991) Divergent molecular pathways of productive and latent infection with a virulent strain of herpes simplex virus type 1. J Virol 65: 4004–4005.Google Scholar
  89. Steele DJ, Auchincloss HJ (1995) Xenotransplantation. Annu Rev Med 46: 345–360.PubMedCrossRefGoogle Scholar
  90. Svendsen CN, Fawcett JW, Bentlage C, Dunnett SB (1995) Increased survival of rat EGF-generated CNS precursor cells using B27 supplemented medium. Exp Brain Res 102: 407–414.PubMedCrossRefGoogle Scholar
  91. Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB (1996) Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol 137: 376–388.PubMedCrossRefGoogle Scholar
  92. Svendsen CN, Caldwell MA, Shen J, ter Borg MG, Rosser AE, Tyers P, Karmiol S, Dunnett SB (1997) Long-term survival of human central nervous system progenitor cells transplanted into rat model of Parkinson’s disease. Exp Neurol 148: 135–146.PubMedCrossRefGoogle Scholar
  93. Takayama H, Ray J, Raymon HK, Baird A, Hogg J, Fisher L, Gage F (1995) Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson’s disease. Nat Med 1: 53–58.PubMedCrossRefGoogle Scholar
  94. Takeuchi Y, Porter CD, Strahan KM, Preece AF, Gustafsson K, Cosset FL, Weiss RA, Collins MKL (1996) Sensitization of cells and retroviruses to human serum by (alphal-3) galactosyltransferase. Nature 379: 85–88.PubMedCrossRefGoogle Scholar
  95. Tearle RG, Tange MJ, Zannettino ZL, Katerelos M, Shinkel TA, Van-Denderen BJ, Lonie AJ, Lyons I, Nottle MB, Cox MB, Becker MB, et al (1996) The alpha-1,3-galactosyltransferase knockout mouse: implications for xenotransplatation. Transplantation 61: 13–19.PubMedCrossRefGoogle Scholar
  96. Wang J, Bankiewics KS, Plunkett RJ, Oldfield EH (1994) Intrastriatal implantation of interleukin-1. J Neurosurg 80: 484–490.PubMedCrossRefGoogle Scholar
  97. Ward T, Pipkin PA, Clarkson NA, Stone DM, Minor PD, Almond JW (1994) Decayaccelerating factor CD55 is identified as the receptor for echovirus 7 using CELICS, a rapid immuno-focal cloning method. EMBO 13: 5070–5074.Google Scholar
  98. Weiss RA (1998) Transgenic pigs and virus adaptation. Nature 391: 327–328.PubMedCrossRefGoogle Scholar
  99. Weiss RA, Reynolds BA, Vescovi AL, Morshead C, Craig CG, van der Kooy D (1996) Is there a neural stem cell in the mammalian forebrain? Trends Neurosci 19: 387–393.PubMedCrossRefGoogle Scholar
  100. Wenning GK, Odin P, Morrish P, Rehncrona S, Widner H, Brundin P, Rothwell JC, Brown R, et al (1997) Short-and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease. Ann Neurol 42: 95–107.PubMedCrossRefGoogle Scholar
  101. Werner ER, Werner-Felmayer G, Fuchs D, Hausen A, Reibnegger D, Yim JJ, Pfleiderer W, Wachter H (1990) Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP-1, and T24 cells. J Biol Chem 265: 3189–3192.PubMedGoogle Scholar
  102. Wolff J (1996) Retraction of Jiao S, Gurevich V, Wolff JA, in Nature 1993 Apr 1;362 (6419):450-453. Nature 380: 734.PubMedCrossRefGoogle Scholar
  103. Wolff J, Fisher L, Xu L, Gage F (1989a) Grafting fibroblasts genetically modified to produce L-dopa in a rat model of Parkinson disease. Proc Natl Acad Sci USA 86: 9011–9014.PubMedCrossRefGoogle Scholar
  104. Wolff J, Fisher L, Xu L, Hyder A, Jinnah H (1989b) Grafting fibroblasts genetically modified to produce L-dopa in a rat model of Parkinson disease. Proc Natl Acad Sci USA 86: 9011–9014.PubMedCrossRefGoogle Scholar
  105. Xiao X, Li J, Samulski JS (1996) Long-term and efficient in vivo gene transfer into muscle tissue of immunocompetent mice with an rAAV vector. J Virol 70: 8098–8108.PubMedGoogle Scholar
  106. Xiao X, Li J, McCown TJ, Samulski JS (1997) Gene transfer by adeno-associated virus vectors into the central nervous system. Exp Neurol 144: 113–124.PubMedCrossRefGoogle Scholar
  107. Yoshimoto Y, Lin Q, Collier TJ, Frim DM, Breakfield XO, Bohn MC (1995) Astrocyts retrovirally transduced with BDNF elicit behavioural improvement in a rat model of Parkinson’s disease. Brain Res 691: 25–36.PubMedCrossRefGoogle Scholar
  108. Zawada WM, Cibelli JB, Choi PK, Clarkson ED, Golueke PJ, Witta SE, Bell KP, Kane J, Ponce De Leon FA, Jerry DJ, Robl JM, Freed CR, Stice SL (1998) Somatic cell cloned transgenic bovine neurons for transplantation in parkinsonian rats. Nat Med 4: 569–574.PubMedCrossRefGoogle Scholar
  109. Zhu SM, Kujirai K, Dollison A, Angulo J, Fahn S, Cadet JL (1992) Implantation of genetically modified mesencephalic fetal cells into rat striatum. Brain Res Bull 29:81–93.PubMedCrossRefGoogle Scholar
  110. Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D (1997) Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotech 15: 871–875.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1999

Authors and Affiliations

  • M. Bauer
    • 1
  • M. Ueffing
    • 2
    • 3
  • T. Meitinger
    • 2
  • T. Gasser
    • 1
  1. 1.Department of Neurology, Klinikum GrosshadernLudwig-Maximilians-UniversityMunichFederal Republic of Germany
  2. 2.Department of Medical GeneticsLudwig-Maximilians-UniversityMunichFederal Republic of Germany
  3. 3.Institute for Molecular Biology and Tumour GeneticsGSFMunichFederal Republic of Germany

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