Coexpression of tyrosine hydroxylase, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter 2 from a helper virus-free herpes simplex virus type 1 vector supports high-level, long-term biochemical and behavioral correction of a rat model of Parkinson's disease.

Parkinson's disease is due to the selective loss of nigrostriatal dopaminergic neurons. Consequently, many therapeutic strategies have focused on restoring striatal dopamine levels, including direct gene transfer to striatal cells, using viral vectors that express specific dopamine biosynthetic enzymes. The central hypothesis of this study is that coexpression of four dopamine biosynthetic and transporter genes in striatal neurons can support the efficient production and regulated, vesicular release of dopamine: tyrosine hydroxylase (TH) converts tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), GTP cyclohydrolase I (GTP CH I) is the rate-limiting enzyme in the biosynthesis of the cofactor for TH, aromatic amino acid decarboxylase (AADC) converts L-DOPA to dopamine, and a vesicular monoamine transporter (VMAT-2) transports dopamine into synaptic vesicles, thereby supporting regulated, vesicular release of dopamine and relieving feedback inhibition of TH by dopamine. Helper virus-free herpes simplex virus type 1 vectors that coexpress the three dopamine biosynthetic enzymes (TH, GTP CH I, and AADC; 3-gene-vector) or these three dopamine biosynthetic enzymes and the vesicular monoamine transporter (TH, GTP CH I, AADC, and VMAT-2; 4-gene-vector) were compared. Both vectors supported production of dopamine in cultured fibroblasts. These vectors were microinjected into the striatum of 6-hydroxydopamine-lesioned rats. These vectors carry a modified neurofilament gene promoter, and gamma-aminobutyric acid (GABA)-ergic neuron-specific gene expression was maintained for 14 months after gene transfer. The 4-gene-vector supported higher levels of correction of apomorphine-induced rotational behavior than did the 3-gene-vector, and this correction was maintained for 6 months. Proximal to the injection sites, the 4-gene-vector, but not the 3-gene-vector, supported extracellular levels of dopamine and dihydroxyphenylacetic acid (DOPAC) that were similar to those observed in normal rats, and only the 4-gene-vector supported significant K(+)-dependent release of dopamine.

[1]  A. Geller,et al.  Improved titers for helper virus-free herpes simplex virus type 1 plasmid vectors by optimization of the packaging protocol and addition of noninfectious herpes simplex virus-related particles (previral DNA replication enveloped particles) to the packaging procedure. , 1999, Human gene therapy.

[2]  H. Federoff,et al.  Helper-free HSV-1 amplicons elicit a markedly less robust innate immune response in the CNS. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[3]  D. Eisenberg,et al.  A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter , 1992, Cell.

[4]  R. Neve,et al.  HSV-1 vector mediated neuronal gene delivery. Strategies for molecular neuroscience and neurology. , 1990, Biochemical pharmacology.

[5]  J. Haycock,et al.  l-Dopa and Dopamine-Producing Gene Cassettes for Gene Therapy Approaches to Parkinson's Disease , 1997, Experimental Neurology.

[6]  S. Wachtel,et al.  Role of Aromatic l‐Amino Acid Decarboxylase for Dopamine Replacement by Genetically Modified Fibroblasts in a Rat Model of Parkinson's Disease , 1997, Journal of neurochemistry.

[7]  J. Naegele,et al.  Long-Term Behavioral Recovery in Parkinsonian Rats by an HSV Vector Expressing Tyrosine Hydroxylase , 1994, Science.

[8]  R. Johnson,et al.  Accumulation of biological amines into chromaffin granules: a model for hormone and neurotransmitter transport. , 1988, Physiological reviews.

[9]  J. Sladek,et al.  Dopamine cell replacement: Parkinson's disease. , 1990, Annual review of neuroscience.

[10]  D. Goldstein,et al.  Improved assay for plasma dihydroxyphenylacetic acid and other catechols using high-performance liquid chromatography with electrochemical detection. , 1994, Journal of chromatography. B, Biomedical applications.

[11]  S. Leff,et al.  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 , 1998, The Journal of Neuroscience.

[12]  R. Wurtman,et al.  Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization , 1980, Brain Research.

[13]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[14]  Ornella Rimoldi,et al.  Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient , 1999, Nature Neuroscience.

[15]  X. Breakefield,et al.  Astrocytes retrovirally transduced with BDNF elicit behavioral improvement in a rat model of Parkinson's disease , 1995, Brain Research.

[16]  Estimation of striatal dopamine spillover and metabolism in vivo , 2000, Neuroreport.

[17]  G. Yancopoulos,et al.  BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra , 1991, Nature.

[18]  K. S. Bankiewicz,et al.  A 6-hydroxydopamine-induced selective parkinsonian rat model , 1989, Brain Research.

[19]  Fenguangzhai Song.  CD , 1992 .

[20]  A. Geller,et al.  General strategy for constructing large HSV-1 plasmid vectors that co-express multiple genes. , 2001, BioTechniques.

[21]  D. Pfaff,et al.  Inflammatory effects of gene transfer into the CNS with defective HSV-1 vectors. , 1994, Gene therapy.

[22]  B. Sahakian,et al.  Circling behavior in rats with partial, unilateral nigro-striatal lesions: Effect of amphetamine, apomorphine, and DOPA , 1980, Pharmacology Biochemistry and Behavior.

[23]  Fred H. Gage,et al.  Partial lesion of the substantia nigra: relation between extent of lesion and rotational behavior , 1991, Brain Research.

[24]  S. Hersch,et al.  Subcellular localization and molecular topology of the dopamine transporter in the striatum and substantia nigra , 1997, The Journal of comparative neurology.

[25]  G. Damsma,et al.  Characterization of dopamine release in the substantia nigra by in vivo microdialysis in freely moving rats , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[26]  H. Federoff,et al.  Immune responses to replication-defective HSV-1 type vectors within the CNS: implications for gene therapy , 2003, Gene Therapy.

[27]  H. Mizukami,et al.  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. , 2000, Human gene therapy.

[28]  M. Matsumura,et al.  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. , 2002, Human gene therapy.

[29]  F. Gage,et al.  Regulation of dopamine production by genetically modified primary fibroblasts , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[30]  E. Werner,et al.  Interleukin 1 beta and cAMP trigger the expression of GTP cyclohydrolase I in rat renal mesangial cells. , 1996, Biochemical Journal.

[31]  R. Neve,et al.  An HSV‐1 Vector Containing the Rat Tyrosine Hydroxylase Promoter Enhances Both Long‐Term and Cell Type‐Specific Expression in the Midbrain , 1997, Journal of neurochemistry.

[32]  P. Wild,et al.  Helper virus-free transfer of herpes simplex virus type 1 plasmid vectors into neural cells , 1996, Journal of virology.

[33]  Andrew Freese,et al.  An HSV‐1 Vector Expressing Tyrosine Hydroxylase Causes Production and Release of l‐DOPA from Cultured Rat Striatal Cells , 1995, Journal of neurochemistry.

[34]  C D Marsden,et al.  Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. , 1990, Science.

[35]  G. Kapatos,et al.  Nigrostriatal Dopamine Neurons Express Low Levels of GTP Cyclohydrolase I Protein , 1998, Journal of Neurochemistry.

[36]  R. J. Mullen,et al.  NeuN, a neuronal specific nuclear protein in vertebrates. , 1992, Development.

[37]  A. Björklund,et al.  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 , 2000, The Journal of Neuroscience.

[38]  A. Björklund,et al.  Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of l-dopa using rAAV-mediated gene transfer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[39]  A. Kingsman,et al.  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. , 2002, The Journal of Neuroscience.

[40]  D. Goldstein,et al.  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. , 2003, Human gene therapy.

[41]  J. Bloch,et al.  Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. , 2000, Science.

[42]  T. Kaneko,et al.  Striatal neurons with aromatic l-amino acid decarboxylase-like immunoreactivity in the rat , 1989, Neuroscience Letters.

[43]  W. Y. Lee,et al.  Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models. , 2001, Human Cell.

[44]  Stephen B. Dunnett,et al.  Functional integration of neural grafts in Parkinson's disease , 1999, Nature Neuroscience.

[45]  S. Wachtel,et al.  Double Transduction with GTP Cyclohydrolase I and Tyrosine Hydroxylase Is Necessary for Spontaneous Synthesis ofl-DOPA by Primary Fibroblasts , 1996, The Journal of Neuroscience.

[46]  O. Isacson.  Behavioral effects and gene delivery in a rat model of Parkinson's disease , 1995, Science.

[47]  J Q Trojanowski,et al.  Transplantation of embryonic dopamine neurons for severe Parkinson's disease. , 2001, The New England journal of medicine.

[48]  H. Ichinose,et al.  Isolation of a full-length cDNA clone for human GTP cyclohydrolase I type 1 from pheochromocytoma , 1995, Journal of Neural Transmission / General Section JNT.

[49]  J. Lile,et al.  GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. , 1993, Science.

[50]  W Zhang,et al.  A tyrosine hydroxylase-neurofilament chimeric promoter enhances long-term expression in rat forebrain neurons from helper virus-free HSV-1 vectors. , 2000, Brain research. Molecular brain research.

[51]  A. Jacobs,et al.  Human gene therapy and imaging in neurological diseases , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[52]  B. Davidson,et al.  Dopaminergic Neurons Protected from Degeneration by GDNF Gene Therapy , 1997, Science.

[53]  H. Sasaki,et al.  Effect of solution composition of plasmid DNA on gene transfection following liver surface administration in mice. , 2005, Biological & pharmaceutical bulletin.

[54]  P. Lang,et al.  Generation of high-titer defective HSV-1 vectors using an IE 2 deletion mutant and quantitative study of expression in cultured cortical cells. , 1996, BioTechniques.

[55]  M. A. Hardwicke,et al.  Evidence that the herpes simplex virus immediate early protein ICP27 acts post-transcriptionally during infection to regulate gene expression. , 1992, Virology.

[56]  G. Kapatos,et al.  Tetrahydrobiopterin Cofactor Biosynthesis: GTP Cyclohydrolase I mRNA Expression in Rat Brain and Superior Cervical Ganglia , 1993, Journal of neurochemistry.

[57]  A. Aguzzi,et al.  Brain cell type specificity and gliosis-induced activation of the human cytomegalovirus immediate-early promoter in transgenic mice , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[58]  P. Fitzpatrick,et al.  Tetrahydropterin-dependent amino acid hydroxylases. , 1999, Annual review of biochemistry.

[59]  Lingxin Kong,et al.  Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson's disease , 2005, Brain Research.

[60]  J. Bolam,et al.  Electron microscopic analysis of D1 and D2 dopamine receptor proteins in the dorsal striatum and their synaptic relationships with motor corticostriatal afferents , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[61]  D. Oorschot.  Total number of neurons in the neostriatal, pallidal, subthalamic, and substantia nigral nuclei of the rat basal ganglia: A stereological study using the cavalieri and optical disector methods , 1996, The Journal of comparative neurology.

[62]  A. Geller,et al.  Enhanced reporter gene expression in the rat brain from helper virus-free HSV-1 vectors packaged in the presence of specific mutated HSV-1 proteins that affect the virion. , 2001, Brain research. Molecular brain research.

[63]  S. Hjorth,et al.  Synthesis and Release of Dopamine in Rat Brain: Comparison Between Substantia Nigra Pars Compacta, Pars Reticulata, and Striatum , 1989, Journal of neurochemistry.

[64]  J. Mallet,et al.  Long-term doxycycline-controlled expression of human tyrosine hydroxylase after direct adenovirus-mediated gene transfer to a rat model of Parkinson's disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[65]  U. Kang,et al.  Vesicular Monoamine Transporter-2 and Aromatic L-amino Acid Decarboxylase Enhance Dopamine Delivery after L-3,4- Dihydroxyphenylalanine Administration in Parkinsonian Rats , 2022 .

[66]  F. Gonon,et al.  Presynaptic regulation of dopaminergic neurotransmission , 2003, Journal of neurochemistry.