Strategies for gene therapy of Parkinson's disease using adeno-associated virus (AAV) vectors

An adeno-associated virus (AAV) vector is a potentially useful gene transfer vehicle for neurologic gene therapy by virtue of its unique characteristics, including lack of any associated disease with wild-type virus, the ability to transduce non-dividing cells, and prolonged expression of the transgene. Parkinson's disease (PD), an appropriate candidate for gene therapy, is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. Current strategies for gene therapy of PD include 1) local production of dopamine in the striatum, and 2) protection of dopaminergic neurons in the substantia nigra. Dopamine is biosynthesized from tyrosine, which is first hydroxylated to L-dopa by tyrosine hydroxylase (TH). L-Dopa is then decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC). Therefore, dopamine would be efficiently produced by the combined use of these dopamine-biosynthesizing enzyme genes. In a rodent model of PD (6-OHDA-lesioned rats), the TH expression in the denervated striatum has been reported to induce behavioral recovery. Since a very limited number of striatal cells produce AADC, we constructed two AAV vectors, AAV-TH and AAV-AADC, and attempted to coexpress both genes in striatal cells to enhance the dopamine synthesis. Lesioned rats were stereotaxically injected with the AAV-TH and/or AAV-AADC vectors into the denervated striatum. As a result, cotransduction with these two AAV vectors caused better behavioral recovery compared with AAV-TH alone. However, this approach can not halt the progressive degeneration of nigral dopaminergic neurons. To prevent dopaminergic neuron death, we are focusing on the protective effects of glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor For dopaminergic neurons. When rat E14 mesencephalic cells were transduced with AAV-GDNF, a larger number of dopaminergic neurons survived in cultures as compared with mock transduction. Furthermore, the dopaminergic neurons in the AAV-GDNF-transduced cultures grew more prominent neurites. Taken together, joint use of these therapeutic strategies, dopamine supplement gene therapy and GDNF gene therapy for protection of dopaminergic neurons, would be a logical approach for the treatment of PD.