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
| Autor: | Robert D. Barber, Mimoun Azzouz, Nicholas D. Mazarakis, Alan J. Kingsman, Enca Martin-Rendon, Susan M. Kingsman, Emma E. Carter, Jonathan Rohll, Kyriacos A. Mitrophanous |
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| Rok vydání: | 2002 |
| Předmět: |
Male
Tyrosine 3-Monooxygenase Dopamine GTP cyclohydrolase I Genetic Vectors Gene Expression Substantia nigra Striatum Biology Kidney chemistry.chemical_compound Catecholamines Parkinsonian Disorders medicine Animals Humans Transgenes ARTICLE Rats Wistar GTP Cyclohydrolase Oxidopamine Cells Cultured Neurons Aromatic L-amino acid decarboxylase Tyrosine hydroxylase General Neuroscience Lentivirus Dopaminergic Gene Transfer Techniques Genetic Therapy Recovery of Function Molecular biology Corpus Striatum Rats Disease Models Animal Treatment Outcome Genes nervous system chemistry Aromatic-L-Amino-Acid Decarboxylases biology.protein medicine.drug |
| Zdroj: | The Journal of Neuroscience. 22:10302-10312 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.22-23-10302.2002 |
| Popis: | Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients. |
| Databáze: | OpenAIRE |
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