Ex Vivo Gene Therapy in the Central Nervous System

  • A. Blesch
  • M. H. Tuszynski
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 155)

Abstract

The targeted delivery of genes into the adult central nervous system (CNS) has received considerable interest in recent years with the development of improved viral vector systems and suitable strategies for therapeutic intervention. Experimental gene therapy in animal models has been studied to prevent or slow the progression of chronic neurodegenerative diseases, to improve recovery after traumatic CNS injury and to kill malignant brain tumors. Genes that have been investigated in these various models include those that code for neurotrophic factors, neurotransmitter synthesis enzymes, modulators of neuronal and glial function, and inducers of cell death. Generally, two different types of gene therapy have been distinguished: in vivo and ex vivo gene therapy. The direct injection of genes into the CNS using viral vectors or DNA-liposome suspensions is termed in vivo gene therapy. Ex vivo gene therapy is based on genetic modification of cells in vitro followed by the grafting of these cells into the CNS. Ex vivo approaches to gene therapy will be the focus of this review.

Keywords

Dopamine Dementia Choline Acetylcholine Tetracycline 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aebischer P, Goddard M, Signore AP, Timpson RL (1994) Functional recovery in hemiparkinsonian primates transplanted with polymer-encapsulated PC12 cells. Exp Neurol 126:151–158PubMedGoogle Scholar
  2. Aebischer P, Pochon NA, Heyd B, Deglon N, Joseph JM, Zurn AD, Baetge EE, Hammang JP, Goddard M, Lysaght M, Kaplan F, Kato AC, Schluep M, Hirt L, Regli F, Porchet F, De Tribolet N (1996b) Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF. Hum Gene Ther 7:851–860PubMedGoogle Scholar
  3. Aebischer P, Schluep M, Déglon N, Joseph JM, Hirt L, Heyd B, Goddard M, Hammang JP, Zurn AD, Kato AC, Regli F, Baetge EE (1996a) Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nature Med 2:696–699PubMedGoogle Scholar
  4. Aebischer P, Tresco PA, Winn SR, Greene LA, Jaeger CB (1991) Long-term cross-species brain transplantation of a polymer-encapsulated dopamine-secreting cell line. Exp Neurol 111:269–275PubMedGoogle Scholar
  5. Alexi T, Venero JL, Hefti F (1997) Protective effects of neurotrophin-4/5 and transforming growth factor-alpha on striatal neuronal phenotypic degeneration after excitotoxic lesioning with quinolinic acid. Neurosci 78:73–86Google Scholar
  6. Anderson KD, Panayotatos N, Corcoran TL, Lindsay RM, Wiegand SJ (1996) Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease. Proc Natl Acad Sci USA 93:7346–7351PubMedGoogle Scholar
  7. Araujo DM, Hilt DC (1997) Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington’s disease. Neurosci 81:1099–1110Google Scholar
  8. Bankiewicz KS, Leff SE, Nagy D, Jungles S, Rokovich J, Spratt K, Cohen L, Libonati M, Snyder RO, Mandel RJ (1997) Practical aspects of the development of ex vivo and in vivo gene therapy for Parkinson’s disease. Exp Neurol 144:147–156PubMedGoogle Scholar
  9. Barba D, Hardin J, Ray J, Gage FH (1993) Thymidine kinase-mediated killing of rat brain tumors. J Neurosurg 79:729–735PubMedGoogle Scholar
  10. Bartus RT, Dean RLD, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414PubMedGoogle Scholar
  11. Beal MF (1994) Neurochemistry and toxin models in Huntington’s disease. Current Opinion Neurol 7:542–547Google Scholar
  12. Beal MF, Ferrante RJ, Swartz KJ, Kowall NW (1991) Chronic quinolinic acid lesions in rats closely resemble Huntington’s disease. J Neurosci 11:1649–1659PubMedGoogle Scholar
  13. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321:168–171PubMedGoogle Scholar
  14. Beck KD, Valverde J, Alexi T, Poulsen K, Moffat B, Vandlen RA, Rosenthal A, Hefti F (1995) Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. Nature 373:339–341PubMedGoogle Scholar
  15. 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 behavioral impairment in a rat model of Parkinson disease. Proc Natl Acad Sci USA 94: 8818–8823PubMedGoogle Scholar
  16. Blesch A, Diergardt N, Tuszynski MH (1998) Cellularly delivered GDNF induces robust growth of motor and sensory axons in the injured adult spinal cord. Soc for Neuroscience Abstracts 24:555Google Scholar
  17. Blesch A, Grill RJ, Tuszynski MH (1998) Neurotrophin gene therapy in CNS models of trauma and degeneration. Progr Brain Res 117:473–484Google Scholar
  18. Blesch A, Tuszynski MH (1995) Ex vivo gene therapy for Alzheimer’s disease and spinal cord injury. Clinical Neurosci 3:268–274Google Scholar
  19. Blesch A, Uy HS, Grill RJ, Cheng JG, Patterson PH, Tuszynski MH (1999) LIF augments corticospinal axon growth and neurotrophin expression after adult CNS injury. J Neurosci 19:3556–3566PubMedGoogle Scholar
  20. Borasio GD, Robberecht W, Leigh PN, Emile J, Guiloff RJ, Jerusalem F, Silani V, Vos PE, Wokke JH, Dobbins T (1998) A placebo-controlled trial of insulin-like growth factor-I in amyotrophic lateral sclerosis. European ALS/IGF-I Study Group. Neurol 51:583–586Google Scholar
  21. Bregman BS, Kunkel-Bagden E, Reier PJ, Dai HN, McAtee M, Gao D (1993) Recovery of function after spinal cord injury: mechanisms underlying transplant-mediated recovery of function differ after spinal cord injury in newborn and adult rats. Exp Neurol 123:3–16PubMedGoogle Scholar
  22. Bregman BS, Kunkel-Bagden E, Schnell L, Dai HN, Gao D, Schwab ME (1995) Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378:498–501PubMedGoogle Scholar
  23. Chen KS, Gage FH (1995) Somatic gene transfer of NGF to the aged brain: behavioral and morphological amelioration. J Neurosci 15:2819–2825PubMedGoogle Scholar
  24. Cheng H, Cao Y, Olson L (1996) Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273:510–513PubMedGoogle Scholar
  25. Choi-Lundberg DL, Lin Q, Chang YN, Chiang YL, Hay CM, Mohajeri H, Davidson BL, Bohn MC (1997) Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275:838–841PubMedGoogle Scholar
  26. Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190PubMedGoogle Scholar
  27. Coyle JT, Schwarcz R (1976) Lesion of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature 263:244–246PubMedGoogle Scholar
  28. Crutcher KA, Collins F (1982) In vitro Evidence for two distinct hippocampal growth factors: basis of neuronal plasticity? Science, 67–68Google Scholar
  29. Culver KW, Ram Z, Wallbridge S, Ishii H, Oldfield EH, Blaese RM (1992) In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256:1550–1552PubMedGoogle Scholar
  30. David S, Aguayo AJ (1981) Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214:931–933PubMedGoogle Scholar
  31. Davies SJ, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390:680–683PubMedGoogle Scholar
  32. Davies SW, Beardsall K (1992) Nerve growth factor selectively prevents excitotoxin induced degeneration of striatal cholinergic neurones. Neurosci Letters 140: 161–164Google Scholar
  33. Déglon N, Heyd B, Tan SA, Joseph JM, Zurn AD, Aebischer P (1996) Central nervous system delivery of recombinant ciliary neurotrophic factor by polymer encapsulated differentiated C2C12 myoblasts. Hum Gene Ther 7:2135–2146PubMedGoogle Scholar
  34. Dunnett SB, Svendsen CN (1993) Huntington’s disease: animal models and transplantation repair. Current Opinion Neurobiol 3:790–796Google Scholar
  35. Dunnett SB, Toniolo G, Fine A, Ryan CN, Björklund A, Iversen SD (1985) Transplantation of embryonic ventral forebrain neurons to the neocortex of rats with lesions of nucleus basalis magnocellularis-II. Sensorimotor and learning impairments. Neurosci 16:787–797Google Scholar
  36. During MJ, Leone P (1997) Targets for gene therapy of Parkinson’s disease: growth factors, signal transduction, and promoters. Exp Neurol 144:74–81PubMedGoogle Scholar
  37. Emerich DF, Hammang JP, Baetge EE, Winn SR (1994) Implantation of polymer-encapsulated human nerve growth factor-secreting fibroblasts attenuates the behavioral and neuropathological consequences of quinolinic acid injections into rodent striatum. Exp Neurol 130:141–150PubMedGoogle Scholar
  38. Emerich DF, Lindner MD, Winn SR, Chen EY, Frydel BR, Kordower JH (1996) Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington’s disease. J Neurosci 16:5168–5181PubMedGoogle Scholar
  39. Emerich DF, Pione M, Francis J, Frydel BR, Winn SR, Lindner MD (1996) Alleviation of behavioral deficits in aged rodents following implantation of encapsulated GDNF-producing fibroblasts. Brain Res 736:99–110PubMedGoogle Scholar
  40. Emerich DF, Winn SR, Hantraye PM, Peschanski M, Chen EY, Chu Y, McDermott P, Baetge EE, Kordower JH (1997) Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 386:395–399PubMedGoogle Scholar
  41. Emerich DF, Winn SR, Harper J, Hammang JP, Baetge EE, Kordower JH (1994) Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: rescue and sprouting of degenerating cholinergic basal forebrain neurons. J Comp Neurol 349:148–164PubMedGoogle Scholar
  42. Ezzeddine ZD, Martuza RL, Platika D, Short MP, Malick A, Choi B, Breakefield XO (1991) Selective killing of glioma cells in culture and in vivo by retrovirus transfer of the herpes simplex virus thymidine kinase gene. New Biologist 3:608–614PubMedGoogle Scholar
  43. Fine A, Dunnett SB, Björklund A, Iversen SD (1985) Cholinergic ventral forebrain grafts into the neocortex improve passive avoidance memory in a rat model of Alzheimer disease. Proc Natl Acad Sci USA 82:5227–5230PubMedGoogle Scholar
  44. Fischer W, Björklund A, Chen K, Gage FH (1991) NGF improves spatial memory in aged rodents as a function of age. J Neurosci 11:1889–1906PubMedGoogle Scholar
  45. Fischer W, Wictorin K, Bjorklund A, Williams LR, Varon S, Gage FH (1987) Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329:65–68PubMedGoogle Scholar
  46. Fisher LJ (1997) Neural precursor cells: applications for the study and repair of the central nervous system. Neurobiol Dis 4:1–22PubMedGoogle Scholar
  47. Fisher LJ, Jinnah HA, Kale LC, Higgins GA, Gage FH (1991) Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce L-dopa. Neuron 6:371–380PubMedGoogle Scholar
  48. Fisher LJ, Raymon HK, Gage FH (1993) Cells engineered to produce acetylcholine: therapeutic potential for Alzheimer’s disease. Ann N Y Acad Sci 695:278–284PubMedGoogle Scholar
  49. Fisher LJ, Schinstine M, Salvaterra P, Dekker AJ, Thal L, Gage FH (1993) In vivo production and release of acetylcholine from primary fibroblasts genetically modified to express choline acetyltransferase. J Neurochem 61:1323–1332PubMedGoogle Scholar
  50. Frim DM, Short MP, Rosenberg WS, Simpson J, Breakefield XO, Isacson O (1993a) Local protective effects of nerve growth factor-secreting fibroblasts against excitotoxic lesions in the rat striatum. J Neurosurg 78:267–273PubMedGoogle Scholar
  51. Frim DM, Simpson J, Uhler TA, Short MP, Bossi SR, Breakefield XO, Isacson O (1993b) Striatal degeneration induced by mitochondrial blockade is prevented by biologically delivered NGF. J Neurosci Res 35:452–458PubMedGoogle Scholar
  52. Frim DM, Uhler TA, Galpern WR, Beal MF, Breakefield XO, Isacson O (1994) Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat. Proc Natl Acad Sci USA 91:5104–5108PubMedGoogle Scholar
  53. Frim DM, Uhler TA, Short MP, Ezzedine ZD, Klagsbrun M, Breakefield XO, Isacson O (1993) Effects of biologically delivered NGF, BDNF and bFGF on striatal excitotoxic lesions. Neuroreport 4:367–370PubMedGoogle Scholar
  54. Gage FH, Armstrong DM, Williams LR, Varon S (1988) Morphological response of axotomized septal neurons to nerve growth factor. J Comp Neurol 269:147–155PubMedGoogle Scholar
  55. Gage FH, Wolff JA, Rosenberg MB, Xu L, Yee JK, Shults C, Friedmann T (1987) Grafting genetically modified cells to the brain: possibilities for the future. Neurosci 23:795–807Google Scholar
  56. Galpern WR, Frim DM, Tatter SB, Altar CA, Beal MF, Isacson O (1996) Cell-mediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration. Cell Transplantat 5:225–232Google Scholar
  57. Galpern WR, Matthews RT, Beal MF, Isacson O (1996) NGF attenuates 3-nitrotyrosine formation in a 3-NP model of Huntington’s disease. Neuroreport 7:2639–2642PubMedGoogle Scholar
  58. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380:252–255PubMedGoogle Scholar
  59. Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551PubMedGoogle Scholar
  60. Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H (1995) Transcriptional activation by tetracyclines in mammalian cells. Science 268:1766–1769PubMedGoogle Scholar
  61. Grill R, Murai K, Blesch A, Gage FH, Tuszynski MH (1997a) Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 17:5560–5572PubMedGoogle Scholar
  62. Grill RJ, Blesch A, Tuszynski MH (1997b) Robust growth of chronically injured spinal cord axons induced by grafts of genetically modified NGF-secreting cells. Exp Neurol 148:444–452PubMedGoogle Scholar
  63. ALS CNTF Treatment Study Group (1996) A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 46:1244–1249Google Scholar
  64. The ALS CNTF Treatment Study (ACTS) Phase III Study Group (1995) A phase I study of recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis. Clin Neuropharmacol 18:515–532Google Scholar
  65. Hefti F (1986) Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 6:2155–2162PubMedGoogle Scholar
  66. Hodges H, Allen Y, Sinden J, Lantos PL, Gray JA (1991) Effects of cholinergic-rich neural grafts on radial maze performance of rats after excitotoxic lesions of the forebrain cholinergic projection system-II. Cholinergic drugs as probes to investigate lesion-induced deficits and transplant-induced functional recovery. Neurosci 45:609–623Google Scholar
  67. Horellou P, Brundin P, Kalen P, Mallet J, Bjorklund A (1990) In vivo release of dopa and dopamine from genetically engineered cells grafted to the denervated rat striatum. Neuron 5:393–402PubMedGoogle Scholar
  68. Horger BA, Nishimura MC, Armanini MP, Wang LC, Poulsen KT, Rosenblad C, Kirik D, Moffat B, Simmons L, Johnson E Jr, Milbrandt J, Rosenthal A, Bjorklund A, Vandlen RA, Hynes MA, Phillips HS (1998) Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons. J Neurosci 18:4929–4937PubMedGoogle Scholar
  69. Hyman C, Hofer M, Barde YA, Juhasz M, Yancopoulos GD, Squinto SP, Lindsay RM (1991) BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350:230–232PubMedGoogle Scholar
  70. Hyman C, Juhasz M, 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 14:335–347PubMedGoogle Scholar
  71. Ikeda K, Wong V, Holmlund TH, Greene T, Cedarbaum JM, Lindsay RM, Mitsumoto H (1995) Histometric effects of ciliary neurotrophic factor in wobbler mouse motor neuron disease. Ann Neurol 37:47–54PubMedGoogle Scholar
  72. Kawaja MD, Rosenberg MB, Yoshida K, Gage FH (1992) Somatic gene transfer of nerve growth factor promotes the survival of axotomized septal neurons and the regeneration of their axons in adult rats. J Neurosci 12:2849–2864PubMedGoogle Scholar
  73. Knüsel B, Beck KD, Winslow JW, Rosenthal A, Burton LE, Widmer HR, Nikolics K, Hefti F (1992) Brain-derived neurotrophic factor administration protects basal forebrain cholinergic but not nigral dopaminergic neurons from degenerative changes after axotomy in the adult rat brain. J Neurosci 12:4391–4402PubMedGoogle Scholar
  74. 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 10:3801–3813PubMedGoogle Scholar
  75. Kordower JH, Chen EY, Mufson EJ, Winn SR, Emerich, DF (1996) Intrastriatal implants of polymer encapsulated cells genetically modified to secrete human nerve growth factor: trophic effects upon cholinergic and noncholinergic striatal neurons. Neurosci 72:63–77Google Scholar
  76. Kordower JH, Chen EY, Winkler C, Fricker R, Charles V, Messing A, Mufson EJ, Wong SC, Rosenstein JM, Björklund A, Emerich DF, Hammang J, Carpenter MK (1997) Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington’s disease. J Comp Neurol 387:96–113PubMedGoogle Scholar
  77. Kordower JH, Winn SR, Liu YT, Mufson EJ, Sladek JR Jr, Hammang JP, Baetge EE, Emerich DF (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 USA 91:10898–10902PubMedGoogle Scholar
  78. Korsching S, Auburger G, Heumann R, Scott J, Thoenen H (1985) Levels of nerve growth factor and its mRNA in the central nervous system of the rat correlate with cholinergic innervation. Embo J 1389–1393Google Scholar
  79. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318PubMedGoogle Scholar
  80. Krieglstein K, Suter-Crazzolara C, Fischer WH, Unsicker K (1995) TGF-beta super-family members promote survival of midbrain dopaminergic neurons and protect them against MPP+ toxicity. Embo J 14:736–742PubMedGoogle Scholar
  81. Kromer LF (1987) Nerve growth factor treatment after brain injury prevents neuronal death. Science 235:214–216PubMedGoogle Scholar
  82. Lange DJ, Felice KJ, Festoff BW, Gawel MJ, Gelinas DF, Kratz R, Lai EC, Murphy MF, Natter HM, Norris FH, Rudnicki S (1996) Recombinant human insulin-like growth factor-I in ALS: description of a double-blind, placebo-controlled study. North American ALS/IGF-I Study Group. Neurology 47:S93–S95Google Scholar
  83. Lapchak PA, Beck KD, Araujo DM, Irwin I, Langston JW, Hefti F (1993) Chronic intranigral administration of brain-derived neurotrophic factor produces striatal dopaminergic hypofunction in unlesioned adult rats and fails to attenuate the decline of striatal dopaminergic function following medial forebrain bundle transection. Neurosci 53:639–650Google Scholar
  84. Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237:1154–1162PubMedGoogle Scholar
  85. 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 a rat model of Parkinson’s disease. J Neurosci 15:7810–7820PubMedGoogle Scholar
  86. Li Y, Field M, Raisman G (1997) Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277:2000–2002PubMedGoogle Scholar
  87. Li Y, Raisman G (1994) Schwann cells induce sprouting in motor and sensory axons in the adult rat spinal cord. J Neurosci 4050–4063Google Scholar
  88. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132PubMedGoogle Scholar
  89. Lin Q, Cunningham LA, Epstein LG, Pechan PA, Short MP, Fleet C, Bohn MC (1997) Human fetal astrocytes as an ex vivo gene therapy vehicle for delivering biologically active nerve growth factor. Hum Gene Ther 8:331–339PubMedGoogle Scholar
  90. Lundberg C, Horellou P, Mallet J, Björklund A (1996) Generation of DOPA-producing astrocytes by retroviral transduction of the human tyrosine hydroxylase gene: in vitro characterization and in vivo effects in the rat Parkinson model. Exp Neurol 139:39–53PubMedGoogle Scholar
  91. Martinez-Serrano A, Björklund A (1996) Protection of the neostriatum against excitotoxic damage by neurotrophin-producing, genetically modified neural stem cells. J Neurosci 16:4604–4616PubMedGoogle Scholar
  92. Martinez-Serrano A, Fischer W, Bjorklund A (1995) Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secreting neural progenitors grafted to the basal forebrain. Neuron 473–484Google Scholar
  93. Martinez-Serrano A, Fischer W, Bjorklund A (1995) Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secreting neural progenitors grafted to the basal forebrain. Neuron 473–484Google Scholar
  94. Martinez-Serrano A, Lundberg C, Horellou P, Fischer W, Bentlage C, Campbell K, McKay RD, Mallet J, Bjorklund A (1995) CNS-derived neural progenitor cells for gene transfer of nerve growth factor to the adult rat brain: complete rescue of axotomized cholinergic neurons after transplantation into the septum. J Neurosci 5668–5680Google Scholar
  95. Martinez-Serrano A, Snyder EY (1999) Neural stem cell lines for CNS repair. In: Tuszynski MH, Kordower JH (eds) CNS Regeneration, (San Diego: Academic Press), pp 203–250Google Scholar
  96. Masliah E, Terry RD, Alford M, DeTeresa R, Hansen LA (1991) Cortical and subcortical patterns of synaptophysinlike immunoreactivity in Alzheimer’s disease. Am J Pathol 138:235–246PubMedGoogle Scholar
  97. McGeer EG, McGeer PL (1976) Duplication of biochemical changes of Huntington’s chorea by intrastriatal injections of glutamic and kainic acids. Nature 263:517–519PubMedGoogle Scholar
  98. McTigue DM, Horner PJ, Stokes BT, Gage FH (1998) Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J Neurosci 18: 5354–5365PubMedGoogle Scholar
  99. Menei P, Montero-Menei C, Whittemore SR, Bunge RP, Bunge MB (1998) Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord. Eur J Neurosci 10:607–621PubMedGoogle Scholar
  100. Milbrandt J, de SFJ, Fahrner TJ, Baloh RH, Leitner ML, Tansey MG, Lampe PA, Heuckeroth RO, Kotzbauer PT, Simburger KS, Golden JP, Davies JA, Vejsada R, Kato AC, Hynes M, Sherman D, Nishimura M, Wang LC, Vandlen R, Moffat B, Klein RD, Poulsen K, Gray C, Garces A, Johnson EM Jr et al. (1998) Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 20:245–253PubMedGoogle Scholar
  101. Miller AD (1990) Retrovirus packaging cells. Hum Gene Ther 1:5–14PubMedGoogle Scholar
  102. Miller AD, Miller DG, Garcia JV, Lynch CM (1993) Use of retroviral vectors for gene transfer and expression. Methods Enzymol 217:581–599PubMedGoogle Scholar
  103. Miller AD, Palmer TD, Hock RA (1986) Transfer of genes into human somatic cells using retrovirus vectors. Cold Spring Harb Symp Quant Biol 51 Pt 2:1013–1019Google Scholar
  104. Miller RG, Petajan JH, Bryan WW, Armon C, Barohn RJ, Goodpasture JC, Hoagland RJ, Parry GJ, Ross MA, Stromatt SC (1996) A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann Neurol 39:256–260PubMedGoogle Scholar
  105. Mitsumoto H, Ikeda K, Holmlund T, Greene T, Cedarbaum JM, Wong V, Lindsay RM (1994) The effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Ann Neurol 36:142–148PubMedGoogle Scholar
  106. Mitsumoto H, Ikeda K, Klinkosz B, Cedarbaum JM, Wong V, Lindsay RM (1994) Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 265:1107–1110PubMedGoogle Scholar
  107. Mori F, Hirnes BT, Kowada M, Murray M, Tessler A (1997) Fetal spinal cord transplants rescue some axotomized rubrospinal neurons from retrograde cell death in adult rats. Exp Neurol 143:45–60PubMedGoogle Scholar
  108. Olson L, Nordberg A, von HH, Backman L, Ebendal T, Alafuzoff I, Amberia K, Hartvig P, Herlitz A, Lilja A et al. (1992) Nerve growth factor affects 11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (case report). J Neural Transm Park Dis Dement Sect 4:79–95PubMedGoogle Scholar
  109. Pardridge WM (1994) New approaches to drug delivery through the blood-brain barrier. Trends Biotechnol 12:239–245PubMedGoogle Scholar
  110. Pérez-Navarro E, Arenas E, Reiriz J, Calvo N, Alberch J (1996) Glial cell line-derived neurotrophic factor protects striatal calbindin-immunoreactive neurons from excitotoxic damage. Neurosci 75:345–352Google Scholar
  111. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 2:1457–1459PubMedGoogle Scholar
  112. Pizzo DL, Paban V, Winkler J, Gage FH, Thal LJ (1998) Characterization of a tetracycline regulatable ChAT fibroblast line. Soc Neurosci Abstracts 24:1055Google Scholar
  113. Price DL (1986) New perspectives on Alzheimer’s disease. Annu Rev Neurosci 9:489–512PubMedGoogle Scholar
  114. Ramon-Cueto A, Nieto-Sampedro M (1994) Regeneration into the spinal cord of transected dorsal root axons is promoted by ensheathing glia transplants. Exp Neurol 127:232–244PubMedGoogle Scholar
  115. Rapalino O, Lazarov-Spiegler O, Agranov E, Velan GJ, Yoles E, Fraidakis M, Solomon A, Gepstein R, Katz A, Belkin M, Hadani M, Schwartz M (1998) Implantation of stimulated homologous macrophages resulkts in partial recovery of paraplegic rats. Nature Med 4:814–821PubMedGoogle Scholar
  116. Richardson PM, McGuinness UM, Aguayo AJ (1980) Axons from CNS neurons regenerate into PNS grafts. Nature 284:264–265PubMedGoogle Scholar
  117. Rosenberg MB, Friedmann T, Robertson RC, Tuszynski M, Wolff JA, Breakefield XO, Gage FH (1988) Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. Science 242:1575–1578PubMedGoogle Scholar
  118. Saffran BN, Woo JE, Mobley WC, Crutcher KA (1989) Intraventricular NGF infusion in the mature rat brain enhances sympathetic innervation of cerebrovascular targets but fails to elicit sympathetic ingrowth. Brain Res 492:245–254PubMedGoogle Scholar
  119. Sagot Y, Tan SA, Baetge E, Schmalbruch H, Kato AC, Aebischer P (1995) Polymer encapsulated cell lines genetically engineered to release ciliary neurotrophic factor can slow down progressive motor neuronopathy in the mouse. Eur J Neurosci 7:1313–1322PubMedGoogle Scholar
  120. Schnell L, Schneider R, Kolbeck R, Barde YA, Schwab ME (1994) Neurotrophin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367:170–173PubMedGoogle Scholar
  121. Schnell L, Schwab ME (1990) Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343:269–272PubMedGoogle Scholar
  122. Schnell L, Schwab ME (1993) Sprouting and regeneration of lesioned corticospinal tract fibres in the adult rat spinal cord. Eur J Neurosci 5:1156–1171PubMedGoogle Scholar
  123. Schwab ME, Otten U, Agid Y, Thoenen H (1979) Nerve growth factor (NGF) in the rat CNS: absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra. Brain Res 168:473–483PubMedGoogle Scholar
  124. Seiler M, Schwab ME (1984) Specific retrograde transport of nerve growth factor (NGF) from neocortex to nucleus basalis in the rat. Brain Res 300:33–39PubMedGoogle Scholar
  125. Selkoe DJ (1996) Cell biology of the beta-amyloid precursor protein and the genetics of Alzheimer’s disease. Cold Spring Harb Symp Quant Biol 61:587–596PubMedGoogle Scholar
  126. Sendtner M, Schmalbruch H, Stöckli KA, Carroll P, Kreutzberg GW, Thoenen H (1992) Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathy. Nature 358:502–504PubMedGoogle Scholar
  127. Sharp AH, Ross CA (1996) Neurobiology of Huntington’s disease. Neurobiol Dis 3:3–15PubMedGoogle Scholar
  128. Shelton DL, Reichardt LF (1986) Studies on the expression of the beta nerve growth factor (NGF) gene in the central nervous system: level and regional distribution of NGF mRNA suggest that NGF functions as a trophic factor for several distinct populations of neurons. Proc Natl Acad Sci USA 83:2714–2718PubMedGoogle Scholar
  129. Smith DE, McCay HL, Gage FH, Roberts JA, Tuszynski MH (1998) Intraparenchymal delivery of NGF by ex vivo gene transfer reverses age-related loss of expression of p75-NTR in basal forebrain cholinergic neurons. Soc Neurosci Abstr 24(1):541Google Scholar
  130. Snyder EY (1994) Grafting immortalized neurons to the CNS. Current Opin Neurobiol 4:742–751Google Scholar
  131. Sobreviela T, Clary DO, Reichardt LF, Brandabur MM, Kordower JH, Mufson EJ (1994) TrkA-immunoreactive profiles in the central nervous system: colocalization with neurons containing p75 nerve growth factor receptor, choline acetyltransferase, and serotonin. J Comp Neurol 350:587–611PubMedGoogle Scholar
  132. Stokes BT, Reier PJ (1992) Fetal grafts alter chronic behavioral outcome after contusion damage to the adult rat spinal cord. Exp Neurol 116:1–12PubMedGoogle Scholar
  133. Takamiya Y, Short MP, Moolten FL, Fleet C, Mineta T, Breakefield XO, Martuza RL (1993) An experimental model of retrovirus gene therapy for malignant brain tumors. J Neurosurg 79:104–110PubMedGoogle Scholar
  134. Terry RD, Katzman R (1983) Senile dementia of the Alzheimer type. Ann Neurol 14:497–506PubMedGoogle Scholar
  135. Tessler A (1991) Intraspinal transplants. Ann Neurol 29:115–123PubMedGoogle Scholar
  136. Tessler A, Fischer I, Giszter S, Hirnes BT, Miya D, Mori F, Murray M (1997) Embryonic spinal cord transplants enhance locomotor performance in spinalized newborn rats. Adv Neurol 72:291–303PubMedGoogle Scholar
  137. Thal L (1994) Clinical trials in Alzheimer disease. In: Terry R, Katzman R, Bick K (eds) Alzheimer disease, (New York: Raven Press), pp 431–444Google Scholar
  138. The-Huntington’s-Disease-Collaborative-Research-Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell 72:971–983Google Scholar
  139. Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, Olson L (1995) Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373:335–339PubMedGoogle Scholar
  140. Tseng JL, Baetge EE, Zurn AD, Aebischer P (1997) GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine. J Neurosci 17:325–333PubMedGoogle Scholar
  141. Tuszynski MH, Gabriel K, Gage FH, Suhr S, Meyer S, Rosetti A (1996b) Nerve growth factor delivery by gene transfer induces differential outgrowth of sensory, motor, and noradrenergic neuntes after adult spinal cord injury. Exp Neurol 137:157–173PubMedGoogle Scholar
  142. Tuszynski MH, Murai K, Blesch A, Grill R, Miller I (1997a) Functional characterization of NGF-secreting cell grafts to the acutely injured spinal cord. Cell Transplant 6:361–368PubMedGoogle Scholar
  143. Tuszynski MH, Peterson DA, Ray J, Baird A, Nakahara Y, Gage FH (1994a) Fibroblasts genetically modified to produce nerve growth factor induce robust neuritic ingrowth after grafting to the spinal cord. Exp Neurol 126:1–14PubMedGoogle Scholar
  144. Tuszynski MH, Roberts J, Senut MC, U HS, Gage FH (1996a) Gene therapy in the adult primate brain: intraparenchymal grafts of cells genetically modified to produce nerve growth factor prevent cholinergic neuronal degeneration. Gene Ther 3:305–314PubMedGoogle Scholar
  145. Tuszynski MH, Sang H, Yoshida K, Gage FH (1991) Recombinant human nerve growth factor infusions prevent cholinergic neuronal degeneration in the adult primate brain. Ann Neurol 30:625–636PubMedGoogle Scholar
  146. Tuszynski MH, Senut MC, Ray J, Roberts J (1994b) Somatic gene transfer to the adult primate central nervous system: In vitro and in vivo characterization of cells genetically modified to secrete nerve growth factor. Neurobiol Dis 1:67–78PubMedGoogle Scholar
  147. Tuszynski MH, U HS, Amarai DG, Gage FH (1990) Nerve growth factor infusion in the primate brain reduces lesion-induced cholinergic neuronal degeneration. J Neurosci 10:3604–3614PubMedGoogle Scholar
  148. Tuszynski MH, Weidner N, McCormack M, Miller I, Powell H, Conner J (1998) Grafts of genetically modified Schwann cells to the spinal cord: survival, axon growth, and myelination. Cell Transplant 7:187–196PubMedGoogle Scholar
  149. Venero JL, Beck KD, Hefti F (1994) Intrastriatal infusion of nerve growth factor after quinolinic acid prevents reduction of cellular expression of choline acetyltransferase messenger RNA and trkA messenger RNA, but not glutamate decarboxylase messenger RNA. Neurosci 61:257–268Google Scholar
  150. Volpe BT, Wildmann J, Altar CA (1998) Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions. Neurosci 83:741–748Google Scholar
  151. Widner H, Brundin P (1988) Immunological aspects of grafting in the mammalian central nervous system. A review and speculative synthesis. Brain Res 472:287–324PubMedGoogle Scholar
  152. Williams LR (1991) Hypophagia is induced by intracerebroventricular administration of nerve growth factor. Exp Neurol 113:31–37PubMedGoogle Scholar
  153. Winkler J, Ramirez GA, Kuhn HG, Peterson DA, Day-Lollini PA, Stewart GR, Tuszynski MH, Gage FH, Thal LJ (1997) Reversible Schwann cell hyperplasia and sprouting of sensory and sympathetic neurites after intraventricular administration of nerve growth factor. Ann Neurol 41:82–93PubMedGoogle Scholar
  154. Winkler J, Suhr ST, Gage FH, Thal LJ, Fisher LJ (1995) Essential role of neocortical acetylcholine in spatial memory. Nature 375:484–487PubMedGoogle Scholar
  155. Wolff JA, Fisher LJ, Xu L, Jinnah HA, Langlais PJ, Iuvone PM, O’Malley KL, Rosenberg MB, Shimohama S, Friedmann T et al. (1989) Grafting fibroblasts genetically modified to produce L-dopa in a rat model of Parkinson disease. Proc Natl Acad Sci USA 86:9011–9014PubMedGoogle Scholar
  156. Xu XM, Chen A, Guenard V, Kleitman N, Bunge MB (1997) Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. J Neurocytol 26:1–16PubMedGoogle Scholar
  157. Xu XM, Guenard V, Kleitman N, Aebischer P, Bunge MB (1995) A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol 134:261–272PubMedGoogle Scholar
  158. Xu XM, Guenard V, Kleitman N, Bunge MB (1994) Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J Comp Neurol 351:145–160Google Scholar
  159. Yankner BA (1996) Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 16:921–932PubMedGoogle Scholar
  160. Ye JH, Houle JD (1997) Treatment of the chronically injured spinal cord with neurotrophic factors can promote axonal regeneration from supraspinal neurons. Exp Neurol 143:70–81PubMedGoogle Scholar
  161. Yoshimoto Y, Lin Q, Collier TJ, Frim DM, Breakefield XO, Bohn MC (1995) Astrocytes retrovirally transduced with BDNF elicit behavioral improvement in a rat model of Parkinson’s disease. Brain Res 691:25–36PubMedGoogle Scholar
  162. Z’Graggen WJ, Metz GA, Kartje GL, Thallmair M, Schwab ME (1998) Functional recovery and enhanced corticofugal plasticity after unilateral pyramidal tract lesion and blockade of myelin-associated neurite growth inhibitors in adult rats. J Neurosci 18:4744–4757PubMedGoogle Scholar
  163. Zeev-Brann AB, Lazarov-Spiegler O, Brenner T, Schwartz M (1998) Differential effects of central and peripheral nerves on macrophages and microglia. Glia 23:181–190PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • A. Blesch
  • M. H. Tuszynski

There are no affiliations available

Personalised recommendations