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
- 10 February 2002
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 13 (3), 345-354
- https://doi.org/10.1089/10430340252792486
Abstract
One potential strategy for gene therapy of Parkinson's disease (PD) is the local production of dopamine (DA) in the striatum induced by restoring DA-synthesizing enzymes. In addition to tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), GTP cyclohydrolase I (GCH) is necessary for efficient DA production. Using adeno-associated virus (AAV) vectors, we previously demonstrated that expression of these three enzymes in the striatum resulted in long-term behavioral recovery in rat models of PD. We here extend the preclinical exploration to primate models of PD. Mixtures of three separate AAV vectors expressing TH, AADC, and GCH, respectively, were stereotaxically injected into the unilateral putamen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys. Coexpression of the enzymes in the unilateral putamen resulted in remarkable improvement in manual dexterity on the contralateral to the AAV-TH/-AADC/-GCH-injected side. Behavioral recovery persisted during the observation period (four monkeys: 48 days, 65 days, 50 days, and >10 months, each). TH-immunoreactive (TH-IR), AADC-IR, and GCH-IR cells were present in a large region of the putamen. Microdialysis demonstrated that concentrations of DA in the AAV-TH/-AADC/-GCH-injected putamen were increased compared with the control side. Our results show that AAV vectors efficiently introduce DA-synthesizing enzyme genes into the striatum of primates with restoration of motor functions. This triple transduction method may offer a potential therapeutic strategy for PD.Keywords
This publication has 35 references indexed in Scilit:
- Convection-Enhanced Delivery of AAV Vector in Parkinsonian Monkeys; In Vivo Detection of Gene Expression and Restoration of Dopaminergic Function Using Pro-drug ApproachExperimental Neurology, 2000
- Cell replacement therapies for central nervous system disordersNature Neuroscience, 2000
- Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in old-world primates one year after MPTP treatmentNeuroscience, 1999
- A new video/computer method to measure the amount of overall movement in experimental animals (two-dimensional object-difference method)Journal of Neuroscience Methods, 1999
- 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 VectorsHuman Gene Therapy, 1998
- In vivo expression of therapeutic human genes for dopamine production in the caudates of MPTP-treated monkeys using an AAV vectorGene Therapy, 1998
- Internalization of D1 Dopamine Receptor in Striatal NeuronsIn Vivoas Evidence of Activation by Dopamine AgonistsJournal of Neuroscience, 1998
- Dopamine Synthesis, Uptake, Metabolism, and Receptors: Relevance to Gene Therapy of Parkinson's DiseaseExperimental Neurology, 1997
- Double Transduction with GTP Cyclohydrolase I and Tyrosine Hydroxylase Is Necessary for Spontaneous Synthesis ofl-DOPA by Primary FibroblastsJournal of Neuroscience, 1996
- l-DOPA and psychosis: Evidence for l-DOPA-induced increases in prefrontal cortex dopamine and in serum corticosteroneBiological Psychiatry, 1995