Abstract
The neuron, unlike many other cells, has a limited capacity for self repair. For this reason, many trials to repair dopaminergic neurons by transplanting new cells have been conducted. Cell replacement therapy for Parkinson's disease (PD), however, has not been realized to date. In vivo gene transduction using viral vectors has become a promising strategy for delivering target genes to the brain; having overtaken ex vivo gene delivery techniques based on superiority in both widespread coverage of target area and long-term gene expression. Employing either a recombinant adeno-associated virus type 2 (AAV2) or a lentivirus vector, four different gene therapy approaches for PD have been tested in humans. In the first, the glutamic acid decarboxylase gene was transferred into the subthalamic nucleus, the currently preferred target for deep brain stimulation, in an attempt to restore normal physiological function of the basal ganglia circuitry. Safety of the AAV2 was confirmed in this phase I trial, and a randomized, blinded phase II trial is currently in progress. The second clinical trial is aimed at protecting the degenerating dopaminergic neurons by putaminal delivery of AAV2- neurturin, a growth factor similar to glial derived neurotrophic factor. Notable improvements were reported in patients in this phase I trial. Neurturin treatment failed, however, to meet the primary end point in a phase II trial because of a placebo effect. The last two approaches focus on increasing dopamine production via direct delivery of genes involved in dopamine synthesis : tyrosine hydroxylase, guanosine triphosphate cyclohydrolase 1, and amino acid decarboxy-lase (AADC). When these three genes are expressed in the putamen, dopamine can be synthesized automatically. Gene transfer of AADC alone in combination with oral levodopa would be a safer strategy. In the latter approach, the patients still need to take levodopa, but excess production of dopamine could be avoided by simply reducing the dose of levodopa. This phase I trial of putaminal injection of AAV2-AADC showed clinical and radiographical improvements in the treated PD patients. The optimal vehicle for delivery of three genes simultaneously into the putamen would be a vector capable of delivering all genes in the same particle. AAV2 is unsuitable in this regard due to its limited packaging capacity. Lentiviral vectors are better suited due to their larger packaging capacity. Recently, a clinical trial of injecting triple genes into the putamen has been started using a lentiviral vector derived from the equine infectious anemia virus.
