GENE THERAPY FOR PARKINSON'S DISEASE: STRATEGIES FOR THE LOCAL PRODUCTION OF DOPAMINE

The cardinal motor symptoms of Parkinson's disease (PD) are associated with the profound depletion of dopamine in the striatum. The replacement of dopamine is the most straightforward strategy to improve motor performance in PD. Researchers have been developing gene therapy aimed at local production of dopamine via the introduction of dopamine-synthesizing enzyme genes into the putamen. Two phase I clinical studies have used recombinant adeno-associated virus (AAV) vectors to transfer the aromatic L-amino acid decarboxylase (AADC) gene into the putamen to restore efficient conversion of orally administered L-3,4-dihydroxyphenylalanine (L-dopa). The initial results of these studies have not only confirmed the safety of AAV vectors, but have also demonstrated the alleviation of motor symptoms associated with PD. Interestingly motor performance in the "off" medication state was improved after gene therapy, suggesting long-term modulation of dopaminergic signals in the striatal neurons was induced by gene transfer. Gene delivery of tyrosine hydroxylase (TH) and guanosine triphosphate cyclohydrolase I (GCH) in addition to AADC may help to avoid motor fluctuations associated with intermittent intake of L-dopa by continuously supplying dopamine in the putamen. A clinical study of such triple gene transfer is presently underway using equine infectious anemia virus (EIAV) vector.