The current status of gene therapy for Parkinson's disease.

The recent development of viral vectors, especially vectors derived from adeno-associated virus (AAV), has translated gene therapy for Parkinson's disease (PD) from animal experiments into clinical trials. The current gene therapy protocols used are based on three major strategies. The first protocol involves local production of dopamine via the introduction of dopamine-synthesizing enzyme genes into the putamen. The aromatic L-amino acid decarboxylase (AADC) gene has been transferred in this manner with the aim of efficiently converting orally administered L-dopa. The delivery of triple genes including tyrosine hydroxylase (TH), guanosine triphosphate cyclohydrolase I (GCH) and AADC is also being undertaken, and is aimed at continuously supplying dopamine into the putamen. The second protocol involves the protection of nigrostriatal projections via the production of neurturin, a trophic factor for dopaminergic neurons in the putamen. The final method includes the modulation of neural activity along the output pathway of the basal ganglia by transducing the subthalamic nucleus with vectors expressing glutamic acid decarboxylase (GAD-65, GAD-67), a key enzyme required for the synthesis of the inhibitory transmitter -aminobutyric acid (GABA). The initial results of phase 1 studies using AAV vectors have not only confirmed the safety of these vectors, but have also revealed the alleviation of motor symptoms associated with PD.