title: 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.
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.
authors.affiliation: Department of Neurology, Jichi Medical School, Tochigi, 329-0498 Japan. muramats@ms.jichi.ac.jp
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Ikeguchi
authors.forename: Nami
authors.initials: N
authors.lastname: Shizuma
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Fumiko
authors.initials: F
authors.lastname: Ono
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kume
authors.forename: Masaru
authors.initials: M
authors.lastname: Matsumura
authors.forename: Ikuko
authors.initials: I
authors.lastname: Nagatsu
authors.forename: Fumi
authors.initials: F
authors.lastname: Urano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nagatsu
authors.forename: Keiji
authors.initials: K
authors.lastname: Terao
authors.forename: Imaharu
authors.initials: I
authors.lastname: Nakano
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics / Q000627:therapeutic use; D000229:Dependovirus; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis*; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000627:therapeutic use; D015316:Genetic Therapy; D005822:Genetic Vectors; D008252:Macaca fascicularis; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D011699:Putamen / Q000502:physiology*; D014161:Transduction, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000627:therapeutic use
chemical_list: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D006136:GTP Cyclohydrolase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine