49. AAV Vector-Mediated Gene Delivery of Aromatic L-Amino Acid Decarboxylase Restored L-DOPA Efficacy in a Primate Bilateral Model of Parkinson's Disease

Parkinson's disease (PD) is a progressive movement disorder marked by selective degeneration of dopaminergic neurons of the substantia nigra and severe decrease in the dopamine (DA) content of the striatum. Replacement of DA is important to alleviate the motor symptoms of the disease. The DA precursor, L-3,4-dihydroxyphenylalanine (L-dopa), which is converted to DA by aromatic L-amino acid decarboxylase (AADC), provides clinical benefit to virtually all patients and has been mainstay in pharmacotherapy for PD. However, as the disease progresses, severe loss of dopaminergic nerve terminals is associated with an 80–95% depletion of striatal AADC activity resulting in loss of L-dopa efficacy. We demonstrated previously that AAV vector-mediated gene transfer of three DA-synthesizing enzymes, namely tyrosine hydroxylase, AADC, and GTP cyclohydrolase I, resulted in behavioral recovery in animal models of PD with efficient and long-term transduction of striatal neurons. In the present experiments, we investigated the therapeutic potential of the combination therapy, gene transfer of AADC with oral administration of L-dopa, in a primate bilateral 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. Animals became behaviorally stable and motor symptoms did not ameliorate by the administration of L-dopa with peripheral AADC inhibitor. Then, adeno-associated virus (AAV) vector expressing AADC was injected into the unilateral putamen stereotaxically. Expression of AADC in the unilateral putamen resulted in remarkable improvement in manual dexterity on the contralateral to the AAV-AADC-injected side after the oral administration of L-dopa with peripheral AADC inhibitor. Fine motor task consists of capturing a piece of an apple improved on the contralateral hand with L-dopa. Amelioration of motor symptoms persisted about four hours each time after the oral intake of L-dopa. This duration of efficacy corresponds to the effective blood concentrations of the drug. Positron emission tomography showed remarkable and persistent increase of [11C]-L-dopa uptake in the AAV-AADC injected putamen. Gene transfer of AADC alone in combination with oral administration of L-dopa could be a shortcut to starting clinical trials of gene therapy for PD. With this method, patients still need to take L-dopa for the control of PD symptoms, but DA production can be regulated by the dose of L-dopa.