[Gene therapy for Parkinson's disease].
Recombinant adeno-associated viral (rAAV) vectors are safer and more effective than other in vivo gene delivery methods. Stereotaxic injection of the vectors provides continuous and selective expression of therapeutic proteins throughout the target area in primate brains without toxicity. Three phase I clinical trials for gene therapy for Parkinson's disease (PD) using rAAV vectors are currently underway. One trial involves gene transfer of aromatic L-amino acid decarboxylase (AADC), an enzyme that converts L-dopa to dopamine, to restore therapeutic windows of orally administered L-dopa in advanced idiopathic PD. After AADC transduction, the daily required dose of L-dopa can be reduced and the duration of the ON period is prolonged. Another trial involves transduction of the subthalamic nucleus (STN) with rAAV vectors expressing glutamic acid decarboxylases, a rate-limiting enzyme for synthesizing inhibitory the neurotransmitter gamma-aminobutyric acid (GABA). This strategy, which is similar to deep brain stimulation, aims at modulating hyperactive STN neurons, thereby alter the resulting activity of down-stream targets, which influence movement. However, the mechanism of stimulation remains unknown, and there are some theoretical concerns of chemical alteration. The other trial involves delivery of rAAV vectors expressing neurturin, a natural analog of a glial cell line-derived neurotrophic factor, into the putamen to slow down the ongoing degeneration of nigral dopaminergic neurons. Positron emission tomography with various tracers has been used to monitor the effects of therapeutic gene expression in vivo. Although no serious adverse effects of gene transfer have been reported so far in these trials, vector systems that regulate transgene expression are necessary to increase safety, and the development of such systems is in progress. Gene therapy using rAAV vectors may be a promising option for treatment of PD in the near future.
Muramatsu
Shin-ichi
S
Division of Neurology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan.
D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D010300:Parkinson Disease / Q000628:therapy*