Gene therapy for Parkinson's disease: Progress and challenges

Current Gene Therapy

Volumn 5, Issue 1, 2005, Pages 71-80

  Chen, Qin ^a,b   He, Yi ^a   Yang, Keyi ^a,b,c  

^a BAYLOR COLLEGE OF MEDICINE   (United States)

^b CENTER FOR CELL AND GENE THERAPY   (United States)

^c MICHAEL E DEBAKEY VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Gene therapy; Glial cell line derived neurotrophic factor; Glutamic acid decarboxylase; Guanosine triphosphate cyclohydrolase I; Helper dependent adenoviral vectors; Parkinsons' disease; Tyrosine hydroxylase; Viral vectors

Indexed keywords

4 AMINOBUTYRIC ACID; 4 AMINOBUTYRIC ACID A RECEPTOR STIMULATING AGENT; ADENOVIRUS VECTOR; AMPHETAMINE; AROMATIC LEVO AMINO ACID DECARBOXYLASE; BETA GALACTOSIDASE; BRAIN DERIVED NEUROTROPHIC FACTOR; COMPLEMENTARY DNA; DOPAMINE; DOPAMINE 2 RECEPTOR; FIBROBLAST GROWTH FACTOR; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; GLUTAMATE DECARBOXYLASE; GUANOSINE TRIPHOSPHATE CYCLOHYDROLASE I; LENTIVIRUS VECTOR; LEVODOPA; LIDOCAINE; MUSCIMOL; NEUROTROPHIC FACTOR; NEUROTROPHIN 4; NEURTURIN; OXIDOPAMINE; PARVOVIRUS VECTOR; PLASMID DNA; PLASMID VECTOR; PLATELET DERIVED GROWTH FACTOR; PROTEIN FOS; RAPAMYCIN; TETRACYCLINE; TYROSINE 3 MONOOXYGENASE; TYROSINE KINASE RECEPTOR; UNINDEXED DRUG; VESICULAR MONOAMINE TRANSPORTER 2; VIRUS PROTEIN; VIRUS VECTOR;

CELL SURVIVAL; DOPAMINE METABOLISM; DOPAMINERGIC NERVE CELL; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DYSKINESIA; GENE EXPRESSION REGULATION; GENE THERAPY; HALLUCINATION; HERPES SIMPLEX VIRUS; HUMAN; NIGRONEOSTRIATAL SYSTEM; NONHUMAN; NONVIRAL GENE DELIVERY SYSTEM; ON OFF PHENOMENON; PARKINSON DISEASE; REVIEW; SIGNAL TRANSDUCTION; STRIATONIGRAL DEGENERATION; STRUCTURE ANALYSIS; VIRAL GENE DELIVERY SYSTEM;

EID: 13844255766     PISSN: 15665232     EISSN: None     Source Type: Journal    
DOI: 10.2174/1566523052997505     Document Type: Review

References (104)

1. Abe K. (2000) Therapeutic potential of neurotrophic factors and neural stem cells against ischemic brain injury. J. Cereb Blood Flow Metab., 20: 1393-1408.
2. Abruzzese, R.V., Godin, D., Burcin, M., Mehta, V., French, M., Li, Y., O'Malley, B.W., and Nordstrom, J.L. (1999) Ligand-dependent regulation of plasmid-based transgene expression in vivo. Hum. Gene Ther., 10: 1499-1507.
3. Abruzzese, R.V., Godin, D., Mehta, V., Perrard, J.L., French, M., Nelson, W., Howell, G., Coleman, M., O'Malley, B.W., and Nordstrom, J.L. (2000) Ligand-dependent regulation of vascular endothelial growth factor and erythropoietin expression by a plasmid-based autoinducible GeneSwitch system. Mol. Ther., 2: 276-287.
4. Airaksinen, M.S., Titievsky, A., and Saarma, M. (1999) GDNF family neurotrophic factor signaling: four masters one servant? Mol. Cell Neurosci., 13: 313-325.
5. Azzouz, M., Martin-Rendon, E., Barber, R.D., Mitrophanous, K.A., Carter, E.E., Rohll, J.B., Kingsman, S.M., Kingsman, A.J., and Mazarakis, N.D. (2002) 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., 22: 10302-10312.
6. Baloh, R.H., Tansey, M.G., Johnson, E.M. Jr., and Milbrandt, J. (2000) Functional mapping of receptor specificity domains of glial cell line-derived neurotrophic factor (GDNF) family ligands and production of GFRalpha1 RET-specific agonists. J. Biol. Chem., 275: 3412-3420.
7. Bankiewicz, K.S., Eberling, J.L., Kohutnicka, M., Jagust, W., Pivirotto, P., Bringas, J., Cunningham, J., Budinger, T.F., and Harvey-White, J. (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: 2-14.
8. Barkats, M., Bilang-Bleuel, A., Buc-Caron, M.H., Castel-Barthe, M.N., Corti, O., Finiels, F., Horellou, P., Revah, F., Sabate, O., and Mallet, J. (1998) Adenovirus in the brain: recent advances of gene therapy for neurodegenerative diseases. Prog. Neurobiol., 55: 333-341.
9. Begany T. (2003) First Parkinson's disease gene therapy administered. Neurology Reviews, 11: 1.
10. Bensadoun, J.C., Deglon, N., Tseng, J.L., Ridet, J.L., Zurn, A.D., and Aebischer, P. (2000) Lentiviral vectors as a gene delivery system in the mouse midbrain: cellular and behavioral improvements in a 6-OHDA model of Parkinson's disease using GDNF. Exp. Neurol., 164: 15-24.
11. Bjorklund, A., Rodenblad, C., Winkler, C., and 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.
12. Bjorklund, A., Kirik, D., Rosenblad, C., Georgievska, B., Lundberg, C., and Mandel, R.J. (2000) Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Brain Research, 886: 82-98.
13. Burcin, M.M., Schiedner, G., Kochanek, S., Tsai, S.Y., and O'Malley, B.W. (1999) Adenovirus-mediated regulable target gene expression in vivo. Proc. Natl. Acad. Sci. USA, 96: 355-360.
14. Cao, L., Zhao, Y.C., Jiang, Z.H., Xu, D.H., Liu, Z.G., Chen, S.D., Liu, X.Y., and Zheng, Z.C. (2000) Long-term phenotypic correction of rodent hemiparkinsonism by gene therapy using genetically modified myoblasts. Gene Ther., 7: 445-449.
15. Choi-Lundberg, D.L., Lin, Q., Chang, Y.N., Chiang, Y.L., Hay, C.M., Mohajeri, H., Davidson, B.L., and Bohn, M.C. (1997) Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science, 275: 838-841.
16. Choi-Lundberg, D.L., Lin, Q., Schallert, T., Crippens, D., Davidson, B.L., Chang, Y.N., Chiang, Y.L., Qian, J., Bardwaj, L., and Bohn, M.C. (1998) Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor. Exp. Neurol., 154: 261-275.
17. Collier, T.J., and Sortwell, C.E. (1999) Therapeutic potential of nerve growth factors in Parkinson's disease. Drugs Aging 14: 261-287.
18. Connor, B., Kozlowski, D.A., Schallert, T., Tillerson, J.L., Davidson, B.L., and Bohn, M.C. (1999) Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged parkinsonian rat. Gene Therapy, 6: 1936-1951.
19. Connor, B., Kozlowski, D.A., Unnerstall, J.R., Elsworth, J.D., Tillerson, J.L., Schallert, T., and Bohn, M.C. (2001). Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects dopaminergic terminals from degerneration. Exp. Neurol., 169: 83-95.
20. Corti, O., Sanchez-Capelo, A., Colin, P., Hanoun, N., Hamon, M., and Mallet, J. (1999) Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson's disease. Proc. Natl. Acad. Sci. USA, 96: 12120-5.
21. Cronin, C.A., Gluba, W., and Scrable, H. (2001) The lac operator-repressor system is functional in the mouse. Genes Dev., 15: 1506-1517.
22. Dave, U.P., Jenkins, N.A., and Copeland, N.G. (2004) Gene therapy insertional mutagenesis insights. Science, 303: 333.
23. Date, I., Aoi, M., Tomita, S., Collins, F., and Ohmoto, T. (1998) GDNF administration induces recovery of the nigrostriatal dopaminergic system both in young and aged parkinsonian mice. Neuroreport, 9: 2365-2369.
24. De Vos, J., Bagnis, C., Bonnafoux, L., Requirand, G., Jourdan, M., Imbert, M.C., Jourdan, E., Rossi, J.F., Mannoni, P., and Klein, B. (2003) Comparison of murine leukemia virus, human immunodeficiency virus, and adeno-associated virus vectors for gene transfer in multiple myeloma: lentiviral vectors demonstrate a striking capacity to transduce low-proliferating primary tumor cells. Hum. Gene Ther., 14: 1727-1739.
25. During, M.J., Kaplitt, M.G., Stern, M.B., and Eidelberg, D. (2001) Subthalamic GAD gene transfer in Parkinson disease patients who are candidates for deep brain stimulation. Hum Gene Ther., 12 1589-1591.
26. Fan, D.S., Ogawa, M., Fujimoto, K.I., Ikeguchi, K., Ogasawara, Y., Urabe, M., Nishizawa, M., Nakano, I., Yoshida, M., Nagatsu, I., Ichinose, H., Nagatsu, T., Kurtzman, G.J., and Ozawa, K. (1998) Behavioral recovery in 6-hydroxydopamine-lesioned rats by cotransduction of striatum with tyrosine- hydroxylase and aromatic L-amino acid decarboxylase genes using two separate adeno-associated virus vectors. Hum. Gene Ther., 9: 2527-2535.
27. Fowler, S.C., Zarcone, T.J., Vorontsova, E., and Chen, R. (2002) Motor and associative deficits in D2 dopamine receptor knockout mice. Int J Dev Neurosci., 20: 309-321.
28. Freed, C.R., Greene, P.E., Breeze, R.E., Tsai, W.Y., DuMouchel, W., Kao, R., Dillon, S., Winfield, H., Culver, S., Trojanowski, J.Q., Eidelberg, D., and Fahn, S. (2001) Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med., 344: 710-719.
29. Georgievska, B., Kirik, D., and Bjorklund, A. (2002) Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer. Exp. Neurol., 177: 461-474.
30. Gill, S.S., Patel, N.K., Hotton, G.R., O'Sullivan, K., McCarter, R., Bunnage, M. Brooks, D.J., Svendsen, C.N., and Heywood, P. (2003) Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med., 9: 589-595.
31. Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., McCormack, M.P., Wulffraat, N., Leboulch, P., Lim, A., Osborne, C.S., Pawliuk, R., Morillon, E., Sorensen, R., Forster, A., Fraser, P., Cohen, J.I., de Saint, Basile, G., Alexander, I., Wintergerst, U., Frebourg, T., Aurias, A., Stoppa-Lyonnet, D., Romana, S., Radford-Weiss, I., Gross, F., Valensi, F., Delabesse, E., Macintyre, E., Sigaux, F., Soulier, J., Leiva, L.E., Wissler, M., Prinz, C., Rabbitts, T.H., Le Deist, F., Fischer, A., and Cavazzana-Calvo, M. (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302: 415-419.
32. Hebert, M.A. and Gerhardt G.A. (1997) Behavioural and neurochemical effects of intranigral administration of glial cell line-derived neurotrophic factor on aged Fischer 344 rats. J. Pharmacol. Exp. Ther., 282: 760-768.
33. Hoane, M.R., Gulwadi, A.G., Morrison, S., Hovanesian, G., Lindner, M.D., and Tao, W. (1999) Differential in vivo effects of neurturin and glial cell-line-derived neurotrophic factor. Exp. Neurol., 160: 235-243.
34. Horellou, P., Vigne, E., Castel, M.N., Barneoud, P., Colin, P., Perricaudet, M., Delaere, P., and 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.
35. Ikari, H., Umegaki, H., and Iguchi, A. (1999) Gene therapy to parkinson's disease. Nippon Ronen Igskkai Zasshi, 36: 103-109.
36. Imaoka, T., Date, I., Ohmoto, T., Yasuda, T., and Tsuda, M. (1998a) In vivo gene transfer into the adult mammalian central nervous system by continuous injection of plasmid DNA-cationic liposome complex. Brain Res., 780: 119-128.
37. Imaoka, T., Date, I., Ohmoto, T., and Nagatsu, T. (1998b) Significant behavioral recovery in Parkinson's disease model by direct intracerebral gene transfer using continuous injection of a plasmid DNA-liposome complex. Hum. Gene Ther., 9: 1093-1102.
38. Jing, S., Wen, D., Yu, Y., Holst, P.L., Luo, Y., Fang, M., Tamir, R., Antonio, L., Hu, Z., Cupples, R., Louis, J.C., Hu, S., Altrock, B.W., and Fox, G.M. (1996) GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell, 85: 1113-1124.
39. Kirik, D., Rosenblad, C., Bjorklund, A., and Mandel, R.J. (2000) Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson's model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. J. Neurosci., 20: 4686-4700.
40. Kirik, D., Georgievska, B., Burger, C., Winkler, C., Muzyczka, N., Mandel, R.J. and Bjorklund, A. (2002) Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAVV-mediated gene transfer. Proc. Natl. Acad. Sci. USA 99: 4708-4713.
41. Kochanek, S., Clemens, P.R., Mitani, K., Chen, H.H., Chan, S., and Caskey, C.T. (1996) A new adenoviral vector: Replacement of all viral coding sequences with 28 kb of DNA independently expressing both full-length dystrophin and beta-galactosidase. Proc. Natl. Acad. Sci. USA, 93: 5731-5736.
42. Kordower, J.H., Palfi, S., Chen, E.Y., Ma, S.Y., Sendera, T., Cochran, E.J., Cochran, E.J., Mufson, E.J., Penn, R., Goetz, C.G., and Comella, C.D. (1999) Clinicopathological findings following intraventricular glial-derived neurotriphic factor treatment in a patient with Parkinson's disease. Ann. Neurol., 46: 419-424.
43. Kordower, J.H., Emborg, M.E., Bloch, J., Ma, S.Y., Chu, Y., Leventhal, L., McBride, J., Chen, E.Y., Palfi, S., Roitberg, B.Z., Brown, W.D., Holden, J.E., Pyzalski, R., Taylor, M.D., Carvey, P., Ling, Z., Trono, D., Hantraye, P., Deglon, N., and Aebischer, P. (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science, 290: 767-773.
44. Kordower, J.H. (2003) In vivo gene delivery of glial cell line--derived neurotrophic factor for Parkinson's disease. Ann. Neurol., 53 Suppl 3: S120-132.
45. Kozlowski, D.A., Connor, B., Tillerson, J.L., Schallert, T., and Bohn, M.C. (2000) Delivery of a GDNF gene into the substantia nigra after a progressive 6-OHDA lesion maintains functional nigrostriatal connections. Exp. Neurol., 166: 1-15.
46. Labandeira-Garcia, J.L., Rozas, G., Lopez-Martin, E., Liste, I., and Guerra, M.J. (1996) Time course of striatal changes induced by 6-hydroxydopamine lesion of the nigrostriatal pathway, as studied by combined evaluation of rotational behaviour and striatal Fos expression. Exp. Brain Res., 108: 69-84.
47. Latchman, D.S and Coffin, R.S. (2000) Viral vectors in the treatment of Parkinson's disease. Mov. Disord., 15: 9-17.
48. Lee, W.Y., Chang, J.W., Nemeth, N.L., and Kang, U.J. (1999) Vesicular monoamine transporter-2 and aromatic L-amino acid decarboxylase enhance dopamine delivery after L-3,4-dihydroxyphenylalanine administration in parkinsonian rats. J. Neurosci., 19: 3266-3274.
49. Leff, S.E., Rendahl, K.G., Spratt, S.K., Kang, U.J., and Mandel, R.J. (1998) In vivo L-DOPA production by genetically modified primary rat fibroblast or 9L gliosarcoma cell grafts via coexpression of GTP cyclohydrolase I with tyrosine hydroxylase. Exp. Neurol., 151: 249-264.
50. Leff, S.E., Spratt, S.K., Snyder, R.O., and Mandel, R.J. (1999) Long-term restoration of striatal L-aromatic amino acid decarboxylase activity using recombinant adeno-associated viral vector gene transfer in a rodent model of Parkinson's disease. Neuroscience 92: 185-196.
51. Levy, R., Lang, A.E., Dostrovsky, J.O., Pahapill, P., Romas, J., Saint-Cyr, J., Hutchison, W.D., and Lozano, A.M. (2001) Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms. Brain, 124: 2105-2118.
52. Li, Z., Dullmann, J., Schiedlmeier, B., Schmidt, M., von Kalle, C., Meyer, J., Forster, M., Stocking, C., Wahlers, A., Frank, O., Ostertag, W., Kuhlcke, K., Eckert, H.G., Fehse, B., and Baum, C. (2002) Murine leukemia induced by retroviral gene marking. Science, 296 497.
53. Lin, L.F.H., Doherty, D.H., Lile, J.D., Bekthesh, S., and Collins, F. (1993) A glial cell-derived neurotrophic factor for midbrain dopaminergic neurons. Science, 260: 1130-1132.
54. Lopez-Real, A., Rodriguez-Pallares, J., Guerra, M.J., and Labandeira-Garcia, J.L. (2003) Localization and functional significance of striatal neurons immunoreactive to aromatic L-amino acid decarboxylase or tyrosine hydroxylase in rat Parkinsonian models. Brain Res., 969: 135-146.
55. Luo, J., Kaplitt, M.G., Fitzsimons, H.L., Zuzga, D.S., Liu, Y., Oshinsky, M.L., and During, M.J. (2002) Subthalamic GAD gene therapy in a Parkinson's disease rat model. Science, 298: 425-429.
56. Mandel, R.J., Spratt, S.K., Snyder, R.O. and Leff, S.E. (1997) Midbrain injection of recombinant adeno-associated virus encoding rat glial cell line-derived neurotrophic factor protects nigral neurons in a progressive 6-hydroxydopamine-induced degeneration model of Parkinson's disease in rats. Proc. Natl. Acad. Sci. USA, 94: 14083-14088.
57. Mandel, R.J., Snyder, R.O., and Leff, S.E. (1999) Recombinant adeno-associated viral vector-mediated glial cell line-derived neurotrophic factor gene transfer protects nigral dopamine neurons after onset of progressive degeneration in the rat model of Parkinson's disease. Exp. Neurol., 160: 205-214.
58. Mastakov, M.Y., Baer, K.,, Symes C.W., Leichtlein, C.B., Kotin, R.M., and During, M.J. (2002) Immunological aspects of recombinant adeno-associated virus delivery to the mammalian brain. J. Virol., 76: 8446-8454.
59. Mitani, K., Graham, F.L., Caskey, C.T., and Kochanek, S. (1995) Rescue, propagation, and partial purification of a helper virus-dependent adenovirus vector. Proc. Natl. Acad. Sci. USA, 92: 3854-3858.
60. Monahan, P.E. and Samulski, R.J. (2000) AAV vectors: is clinical success on the horizon? Gene Ther., 7: 24-30.
61. Morral, N., Parks, R.J., Zhou, H., Langston, C., Schiedner, G., Quinones, J., Graham, F.L., Kochanek, S., and Beaudet, A.L. (1998) High doses of a helper-dependent adenoviral vector yield supraphysiological levels of alpha1-antitrypsin with negligible toxicity. Hum. Gene Ther., 9: 2709-2716.
62. Morsy, M.A., Gu, M., Motzel, S., Zhao, J., Lin, J., Su, Q., Allen, H., Franlin, L., Parks, R.J., Graham, F.L., Kochanek, S., Bett, A.J., and Caskey, C.T. (1998) An adenoviral vector deleted for all viral coding sequences results in enhanced safety and extended expression of a leptin transgene. Proc. Natl. Acad. Sci. USA, 95: 7866-7871.
63. Muramatsu, S., Wang, L., Ikeguchi, K., Fujimoto, K., Nakano, I., and Ozawa, K. (2002a) Recombinant adeno-associated viral vectors bring gene therapy for Parkinson's disease closer to reality. J. Neurol., 249: (Suppl 2): 36-40.
64. Muramatsu, S., Fujimoto, K., Ikeguchi, K., Shizuma, N., Kawasaki, K., Ono, F., Shen, Y., Wang, L., Mizukami, H., Kume, A., Matsumura, M., Nagatsu, I., Urano, F., Ichinose, H., Nagatsu, T., Terao, K., Nakano, I., and Ozawa, K. (2002b) Behavioral recovery in a primate model of Parkinson's disease by triple transduction of striatal cells with adeno-associated viral vectors expressing dopamine-synthesizing enzymes. Hum. Gene Ther., 13: 345-354.
65. Murer, M.G., Dziewczapolski, G., Salin, P., Vila, M., Tseng, K.Y., Ruberg, M., Rubinstein, M., Kelly, M.A., Grandy, D.K., Low, M.J., Hirsch, E., Raisman-Vozari, R., and Gershanik, O. (2000) The indirect basal ganglia pathway in dopamine D (2) receptor-deficient mice. Neuroscience, 99: 643-650.
66. Nagatsu, T. and Ichinose, H. (1997) GTP cyclohydrolase I gene, dystonia, juvenile parkinsonism, and Parkinson's disease. J. Neural. Transm., Suppl. 49: 203-209.
67. Nagatsu, T. and Ichinose, H. (1999) Molecular biology of catecholamine-related enzymes in relation to Parkinson's disease. Cell. Mol. Neurobiol., 19: 57-66.
68. Nirenberg, M.J., Chan, J., Liu, Y., Edwards, R.H., and Pickel, V.M. (1996) Ultrastructural localization of the vesicular monoamine transporter-2 in midbrain dopaminergic neurons: potential sites for somatodendritic storage and release of dopamine. J. Neurosci., 16: 4135-4145.
69. Nutt, J.G., Burchiel, K.J., Comella, C.L., Jankovic, J., Lang, A.E., Laws, E.R. Jr., Lozano, A.M., Penn, R.D., Simpson, R.K. Jr., Stacy, M., and Wooten, G.F.; ICV GDNF Study Group. (2003) Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology, 60: 69-73.
70. O'Neal, W.K., Zhou, H., Morral, N., Langston, C., Parks, R.J., Graham, F.L., Kochanek, S., and Beaudet, A.L. (2000) Toxicity associated with repeated administration of first-generation adenovirus vectors does not occur with a helper-dependent vector. Mol. Med., 6: 179-195.
71. Overstall, P.W., and Clarke, C.E. (2002) Uncertainties in the pharmacotherapy of Parkinson's disease and how to solve them. Gerontology, 48: 30-33.
72. Palfi, S., Leventhal, L., Chu, Y., Ma, S.Y., Emborg, M., Bakay, R., Deglon, N., Hantraye, P., Aebischer, P., and Kordower, J.H. (2002) Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration. J. Neurosci., 22: 4942-4954.
73. Pandya, S., Klimatcheva, E., and Planelles, V. (2001) Lentivirus and foamy virus vectors: novel gene therapy tools. Expert. Opin. Biol. Ther., 1: 17-40.
74. Parks RJ. (2000) Improvements in adenoviral vector technology: overcoming barriers for gene therapy. Clin. Genet., 58: 1-11.
75. Peel, A.L. and Klein, R.L. (2000) Adeno-associated virus vectors: activity and applications in the CNS. J. Neurosci. Methods 98: 95-104.
76. Piccini, P., Brooks, D.J., Bjorklund, A., Gunn, R.N., Grasby, P.M., Rimoldi, O., Brundin, P., Hagell, P., Rehncrona, S., Widner, H., and Lindvall, O. (1999) Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient. Nat. Neurosci., 2: 1137-1140.
77. Quinonez, R. and Sutton, R.E. (2002) Lentiviral vectors for gene delivery into cells. DNA Cell. Biol., 21: 937-951.
78. Rivera, V.M., Ye, X., Courage, N.L., Sachar, J., Cerasoli, F. Jr., Wilson, J.M., and Gilman, M. (1999) Long-term regulated expression of growth hormone in mice after intramuscular gene transfer. Proc. Natl. Acad. Sci. USA, 96: 8657-8662.
79. Rosenblad, C., Kirik, D., Devaux, B., Moffat, B., Phillips, H.S., and Bjorklund, A. (1999) Protection and regeneration of nigral dopaminergic neurons by neurturin or GDNF in a partial lesion model of Parkinson's disease after administration into the striatum or the lateral ventricle. Eur. J. Neurosci., 11: 1554-1566.
80. Rosenblad, C., Georievska, B., and Kirik, D. (2003) Long-term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system. Eur. J. Neurosci., 17: 260-270.
81. Rosenstein J.M. (1995) Why do neural transplants survive? An examination of some metabolic and pathophysiological considerations in neural transplantation. Exp. Neurol., 133: 1-6.
82. Saarma M. (2000) GDNF - a stranger in the TGF-β superfamily? Eur. J. Biochem., 267: 6968-6971.
83. Sanchez-Pernaute, R., Harvey-White, J., Cunningham, J. and Bankiewicz, K.S. (2001) Functional effect of adeno-associated virus mediated gene transfer of aromatic L-amino acid decarboxylase into the striatum of 6-OHDA-lesioned rats. Mol. Ther., 4: 324-330.
84. Sandig, V., Youil, R., Bett, A.J., Franlin, L.L., Oshima, M., Maione, D., Wang, F., Metzker, M.L., Savino, R., and Caskey, C.T. (2000) Optimization of the helper-dependent adenovirus system for production and potency in vivo. Proc. Natl. Acad. Sci. USA, 97: 1002-7.
85. Salin, P., Manrique, C., Forni, C., and Kerkerian-Le, Goff L. (2002) High-frequency stimulation of the subthalamic nucleus selectively reverses dopamine denervation-induced cellular defects in the output structures of the basal ganglia in the rat. J. Neurosci., 22: 5137-5148.
86. Sato, M., Suzuki, S., Kubo, S., and Mitani, K. (2002) Replication and packaging of helper-dependent adenoviral vectors. Gene Ther., 9: 472-476.
87. Schiedner, G., Morral, N., Parks, R.J., Wu, Y., Koopmans, S.C., Langston, C., Graham, F.L., Beaudet, A.L., and Kochanek, S. (1998) Genomic DNA transfer with a high-capacity adenovirus vector results in improved in vivo gene expression and decreased toxicity. Nat. Genet. 18: 180-183.
88. Schwarz, E.J., Alexander, G.M., Prockop, D.J. and Azizi, S.A. (1999) Multipotential marrow stromal cells transduced to produce L-DOPA: Engraftment in a rat model of Parkinson disease. Hum. Gene Ther., 10: 2539-2549.
89. Shen, Y., Muramatsu, S.I., Ikeguchi, K., Fujimoto, K.I., Fan, D.S., Ogawa, M., Mizukami, H., Urabe, M., Kume, A., Nagatsu, I., Urano, F., Suzuki, T., Ichinose, H., Nagatsu, T., Monahan, J., Nakano, I., and Ozawa, K. (2000) 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., 11: 1509-1519.
90. Stromberg, I., Bjorklund, L., Johansson, M., Tomac, A., Collins, F., Olson, L., Hoffer, B., Humpel, C. (1993) Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp. Neurol., 124: 401-412.
91. Sun, M., Zhang, G.R., Kong, L., Holmes, C., Wang, X., Zhang, W., Goldstein, D.S., and Geller, A.I. (2003) Correction of a rat model of Parkinson's disease by coexpression of tyrosine hydroxylase and aromatic amino acid decarboxylase from a helper virus-free herpes simplex virus type 1 vector. Hum. Gene Ther., 14: 415-424.
92. Tomac, A., Lindqvist, E., Lin, L.F., Ogren, S.O., Young, D., Hoffer, B.J., and Olson, L. (1995) Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature, 373 335-339.
93. Wachtel, S.R., Bencsics, C., and Kang, U.J. (1997) The role of aromatic L-amino acid decarboxylase for dopamine replacement by genetically modified fibroblasts in a rat model of Parkinson's disease. J. Neurochem., 69: 2055-2063.
94. Wang, Y., Xu, R., Sasaoka, T., Tonegawa, S., Kung, M.P., and Sankoorikal, E.B. (2000) Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions. J. Neurosci., 20 8305-8314.
95. Wang, L., Muramatsu, S., Lu, Y., Ikeguchi, K., Fujimoto, K., Okada, T., Mizukami, H., Hanazone, Y., Kume, A., Urano, F., Ichinose, H., Nagatsu, T., Nakano, I., and Ozawa, K. (2002) Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease. Gene Ther., 9 381-389.
96. Weber, W., Kramer, B.P., Fux, C., Keller, B., and Fussenegger, M. (2002) Novel promoter/transactivator configurations for macrolide- and streptogramin-responsive transgene expression in mammalian cells. J. Gene Med., 4: 676-686.
97. Wichmann, T., Kliem, M.A., and DeLong, M.R. (2001) Antiparkinsonian and behavioral effects of inactivation of the substantia nigra pars reticulata in hemiparkinsonian primates. Exp. Neurol., 167: 410-424.
98. Windels, F., Bruet, N., Poupard, A., Feuerstein, C., Bertrand, A,. and Savasta, M. (2003) Influence of the frequency parameter on extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats. J. Neurosci. Res., 72: 259-267.
99. Wood, M.J., Charlton, H.M., Wood, K.J., Kajiwara, K., and Byrnes, A.P. (1996) Immune responses to adenovirus vectors in the nervous system. Trends Neurosci., 19: 497-501.
100. Xiao, H., Hirata, Y., Isobe, K., and Kiuchi, K. (2002) Glial cell line-derived neurotrophic factor up-regulates the expression of tyrosine hydroxylase gene in human neuroblastoma cell lines. J. Neurochem., 82: 801-808.
101. Ye, X., Schillinger, K., Burcin, M.M., Tsai, S.Y., and O'Malley, B.W. (2002) Ligand-inducible transgene regulation for gene therapy. Methods Enzymol., 346: 551-561.
102. Zhou, H.S., Zhao, T., Rao, X.M., and Beaudet, A.L. (2002) Production of helper-dependent adenovirus vector relies on helper virus structure and complementing. J. Gene Med., 4: 498-509.
103. Zou, L., Zhou, H., Pastore, L., and Yang, K. (2000) Prolonged transgene expression mediated by a helper-dependent adenoviral vector (hdAd) in the central nervous system. Mol. Ther., 2: 105-113.
104. Zou, L., Yuan, X., Zhou, H., Lu, H., and Yang, K. (2001) Helper-dependent adenoviral vector-mediated gene transfer in aged rat brain. Hum. Gene Ther., 12: 181-191.