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.
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.
Muramatsu
Shin-Ichi
S
Department of Neurology, Jichi Medical School, Tochigi, 329-0498 Japan. muramats@ms.jichi.ac.jp
Fujimoto
Ken-Ichi
K
Ikeguchi
Kunihiko
K
Shizuma
Nami
N
Kawasaki
Katsuyoshi
K
Ono
Fumiko
F
Shen
Yang
Y
Wang
Lijun
L
Mizukami
Hiroaki
H
Kume
Akihiro
A
Matsumura
Masaru
M
Nagatsu
Ikuko
I
Urano
Fumi
F
Ichinose
Hiroshi
H
Nagatsu
Toshiharu
T
Terao
Keiji
K
Nakano
Imaharu
I
Ozawa
Keiya
K
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
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