BEHAVIORAL RECOVERY IN 6-HYDROXYDOPAMINE-LESIONED RATS BY COTRANSDUCTION OF STRIATUM WITH TYROSINE-HYDROXYLASE AND AROMATIC L-AMINO-ACID DECARBOXYLASE GENES USING 2 SEPARATE ADENOASSOCIATED VIRUS VECTORS

Parkinson's disease (PD) is characterized by the progressive loss of t he dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum, A promising approach to the gene therapy of PD is intrastriatal expression of enzymes in the biosynthetic pathw ay for dopamine, Tyrosine hydroxylase (TH) catalyzes the synthesis of L-dopa, which must be converted to dopamine by aromatic L-amino acid d ecarboxylase (AADC), Since the endogenous AADC activity in the striatu m is considered to be low, coexpression of both TH and AADC in the sam e striatal cells would increase the dopamine production and thereby au gment the therapeutic effects. In the present study, the TH gene and a lso the AADC gene were simultaneously transduced into rat striatal cel ls, using two separate adeno-associated virus (AAV) vectors, AAV-TH an d AAV-AADC, Immunostaining showed that TH and AADC were coexpressed ef ficiently in the same striatal cells in vitro and lit vivo. Moreover, cotransduction with these two AAV vectors resulted in more effective d opamine production and more remarkable behavioral recovery in 6-hydrox ydopamine (6-OHDA)-lesioned rats, compared with rats receiving AAV-TH alone (p < 0.01). These findings suggest an alternative strategy for g ene therapy of PD and indicate that the simultaneous transduction with two AAV vectors can extend their utility for potential gene therapy a pplications.