 |
||||
|
||||
|
||||
|
||||
.gif?ad=17923&adview=true)
Previous Article | Next Article
The Journal of Neuroscience, June 1, 1998, 18(11):4271-4284
Characterization of Intrastriatal Recombinant Adeno-Associated Virus-Mediated Gene Transfer of Human Tyrosine Hydroxylase and Human GTP-Cyclohydrolase I in a Rat Model of Parkinson's Disease
R. J. Mandel, K. G. Rendahl, S. K. Spratt, R. O. Snyder, L. K. Cohen, and S. E. Leff Department of Gene Therapy Applications, Cell Genesys Inc., Foster City, California 94404
To achieve local, continuous L-DOPA delivery in the striatum by gene replacement as a model for a gene therapy for Parkinson's disease, the present studies used high titer purified recombinant adeno-associated virus (rAAV) containing cDNAs encoding human tyrosine hydroxylase (hTH) or human GTP-cyclohydrolase I [GTPCHI, the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis] or both to infect the 6-OHDA denervated rat striatum. Striatal TH and GTPCHI staining was observed 3 weeks after rAAV transduction, with little detectable perturbation of the tissue. Six months after intrastriatal rAAV transduction, TH staining was present but apparently reduced compared with the 3 week survival time. In a separate group of animals, striatal TH staining was demonstrated 1 year after rAAV transduction. Double staining studies using the neuronal marker NeuN indicated that >90% of rAAV-transduced cells expressing hTH were neurons. Microdialysis experiments indicated that only those lesioned animals that received the mixture of MD-TH and MD-GTPCHI vector displayed BH4 independent in vivo L-DOPA production (mean ~4-7 ng/ml). Rats that received the hTH rAAV vector alone produced measurable L-DOPA (mean ~1-4 ng/ml) only after receiving exogenous BH4. L-Aromatic amino acid decarboxylase blockade, but not 100 mM KCl-induced depolarization, enhanced L-DOPA overflow, and animals in the non-hTH groups (GTPCHI and alkaline phosphatase) yielded minimal L-DOPA. Although elevated L-DOPA was observed in animals that received mixed hTH and hGTPCHI rAAV vectors, there was no reduction of apomorphine-induced rotational behavior 3 weeks after intrastriatal vector injection. These data demonstrate that purified rAAV, a safe and nonpathogenic viral vector, mediates long-term striatal hTH transgene expression in neurons and can be used to successfully deliver L-DOPA to the striatum.
Key words: recombinant adeno-associated virus; tyrosine hydroxylase; GTP-cyclohydrolase I; gene therapy; Parkinson's disease; L-dihydroxyphenylalanine
Copyright © 1998 Society for Neuroscience 0270-6474/98/18114271-14$05.00/0
This article has been cited by other articles:
B. Dass, C. W. Olanow, and J. H. Kordower
Gene transfer of trophic factors and stem cell grafting as treatments for Parkinson's disease
Neurology, May 23, 2006; 66(10_suppl_4): S89 - S103.
[Abstract] [Full Text]
T. Carlsson, C. Winkler, C. Burger, N. Muzyczka, R. J. Mandel, A. Cenci, A. Bjorklund, and D. Kirik
Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors
Brain, March 1, 2005; 128(3): 559 - 569.
[Abstract] [Full Text] [PDF]
C. S. Peden, C. Burger, N. Muzyczka, and R. J. Mandel
Circulating Anti-Wild-Type Adeno-Associated Virus Type 2 (AAV2) Antibodies Inhibit Recombinant AAV2 (rAAV2)-Mediated, but Not rAAV5-Mediated, Gene Transfer in the Brain
J. Virol., June 15, 2004; 78(12): 6344 - 6359.
[Abstract] [Full Text] [PDF]
M. Azzouz, E. Martin-Rendon, R. D. Barber, K. A. Mitrophanous, E. E. Carter, J. B. Rohll, S. M. Kingsman, A. J. Kingsman, and N. D. Mazarakis
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., December 1, 2002; 22(23): 10302 - 10312.
[Abstract] [Full Text] [PDF]
B. A. Habecker, M. G. Klein, N. C. Sundgren, W. Li, and W. R. Woodward
Developmental Regulation of Neurotransmitter Phenotype through Tetrahydrobiopterin
J. Neurosci., November 1, 2002; 22(21): 9445 - 9452.
[Abstract] [Full Text] [PDF]
D. Kirik, C. Rosenblad, C. Burger, C. Lundberg, T. E. Johansen, N. Muzyczka, R. J. Mandel, and A. Bjorklund
Parkinson-Like Neurodegeneration Induced by Targeted Overexpression of alpha -Synuclein in the Nigrostriatal System
J. Neurosci., April 1, 2002; 22(7): 2780 - 2791.
[Abstract] [Full Text] [PDF]
D. Kirik, B. Georgievska, C. Burger, C. Winkler, N. Muzyczka, R. J. Mandel, and A. Bjorklund
Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer
PNAS, March 21, 2002; (2002) 62047599.
[Abstract] [Full Text] [PDF]
M. A. Passini and J. H. Wolfe
Widespread Gene Delivery and Structure-Specific Patterns of Expression in the Brain after Intraventricular Injections of Neonatal Mice with an Adeno-Associated Virus Vector
J. Virol., December 15, 2001; 75(24): 12382 - 12392.
[Abstract] [Full Text] [PDF]
D. Lau, L. H. McGee, S. Zhou, K. G. Rendahl, W. C. Manning, J. A. Escobedo, and J. G. Flannery
Retinal Degeneration Is Slowed in Transgenic Rats by AAV-Mediated Delivery of FGF-2
Invest. Ophthalmol. Vis. Sci., October 1, 2000; 41(11): 3622 - 3633.
[Abstract] [Full Text]
D. Kirik, C. Rosenblad, A. Bjorklund, and R. J. Mandel
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., June 15, 2000; 20(12): 4686 - 4700.
[Abstract] [Full Text] [PDF]
C. H. Miao, H. Nakai, A. R. Thompson, T. A. Storm, W. Chiu, R. O. Snyder, and M. A. Kay
Nonrandom Transduction of Recombinant Adeno-Associated Virus Vectors in Mouse Hepatocytes In Vivo: Cell Cycling Does Not Influence Hepatocyte Transduction
J. Virol., April 15, 2000; 74(8): 3793 - 3803.
[Abstract] [Full Text]
O. Corti, A. Sanchez-Capelo, P. Colin, N. Hanoun, M. Hamon, and J. Mallet
Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson's disease
PNAS, October 12, 1999; 96(21): 12120 - 12125.
[Abstract] [Full Text] [PDF]
W. Y. Lee, J. W. Chang, N. L. Nemeth, and U. J. Kang
Vesicular Monoamine Transporter-2 and Aromatic L-Amino Acid Decarboxylase Enhance Dopamine Delivery after L-3,4-Dihydroxyphenylalanine Administration in Parkinsonian Rats
J. Neurosci., April 15, 1999; 19(8): 3266 - 3274.
[Abstract] [Full Text] [PDF]
B. L. Davidson, C. S. Stein, J. A. Heth, I. Martins, R. M. Kotin, T. A. Derksen, J. Zabner, A. Ghodsi, and J. A. Chiorini
From the Cover: Recombinant adeno-associated virus type 2, 4, and 5 vectors: Transduction of variant cell types and regions in the mammalian central nervous system
PNAS, March 28, 2000; 97(7): 3428 - 3432.
[Abstract] [Full Text] [PDF]
D. Kirik, B. Georgievska, C. Burger, C. Winkler, N. Muzyczka, R. J. Mandel, and A. Bjorklund
Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer
PNAS, April 2, 2002; 99(7): 4708 - 4713.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|