| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Recombinant adeno-associated virus (AAV) vector-mediated gene transfer of tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and guanosine triphosphate cyclohydrolase 1 (GCH), which are dopamine (DA)-synthesizing enzymes, provided behavioral recovery in a primate model of Parkinson's disease (PD) with efficient and long-term transduction of striatal neurons. We applied positron emission tomography (PET) to assess trangene-mediated DA synthesis in vivo in a primate model of PD. Cynomolgus macaques (Macaca fascicularis) were chronically treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to make bilateral striatal lesions. After the animals had been behaviorally stable for at least two months, mixtures of AAV vectors expressing the DA-synthesizing enzymes were injected into the unilateral putamen stereotaxically. Use of [^<11>C], a short half-life (20 min) tracer, has made it possible to obtain sequential imaging data, not only during the early steps of D
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A metabolism, but also during DA receptor binding and DA transporter availability in the same subject on the same day. In the AAV vector-injected putamen, remarkable and persistent increase of [^<11>C]L-dopa uptake was observed, reflecting restoration of AADC activity, while bindings of [^<11>C]2_-carbomethoxy-3_(4-fluorophenyl)tropane (_-CFT), DA transporter ligand, and [^<11>C] raclopride, a selective D_2-like receptor antagonist, remained unchanged. DA receptor availability to [^<11>C] raclopride was significantly reduced in the AAV vector-injected putamen following L-dopa administration, suggesting additional synthesis of DA in response to the exogenous L-dopa.
A recombinant adeno-associated virus (AAV) vector that expressing Cre recombinase fused to a mutated ligand binding domain of estrogen receptor _(CreER^<T2>) was delivered along with AAV vectors that expressing dopamine-synthesizing enzymes to rats with a model of Parkinson's disease. Treatment with 4-hydroxytamoxifen, a synthetic estrogen receptor modulator, activated the Cre recombinase in the transduced neurons and induced selective excision of the tyrosine hydroxylase (TH) coding sequence that was flanked by loxP sites, leading to the reduction of transgene-mediated dopamine synthesis. Less
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