부산대학교 도서관

Parkinson's disease (PD) is a movement disorder characterized by difficuly initiating movements (bradykinesia), muscular rigidity and tremor. This is associated with pathologically increased activity of the subthalamic nucleus (STN) and the downstream globu pallidus interna (GPi) leading reduced activity of pre-motor cortex (PMC). To normalize this pattern of activity, the STN was injected unilaterally with an adeno-associated virus vector expressing glutamic acid decarboxylase (AAV-GAD) in 12 patients with advanced PD, while the untreated side served as a control. GAD is the rate-limiting step in the synthesis of GABA, the major inhibitory neurotransmitter in the normal brain. Patients were divided into 3 groups of 4, and each group receiving 35μl of 1011(low), 3×1011(middle) or 1012(high-dose) packaged genomes/ml. All 12 patients have now been followed for 6 months. There have been no study-related adverse events. 2 patients had high neutralizing antibody titers prior to surgery, but there was no change in titers in any patient following treatment. Using the standard Unified Parkinson's disease rating scale (UPDRS), there was an overall significant reduction in total UPDRS at 6 months compared with preop (p<0.01); this was mostly due to a roughly 35% improvement in the side contralateral to the treated side (p<0.02) with no signficant change in the other side. There appeared to be a dose effect, as the low dose group had only a slight reduction while the high dose group averaged nearly 50% reduction in UPDRS. Functional brain activity, as measured by glucose PET, showed similar changes. Pathological hypermetabolism of GPi was significantly reduced on the treated side of the brain (p<0.001) while PMC activity correspondingly increased with a highly significant correlation (r-0.78,P<0.00) with improvements in clinical ratings in a dose-dependent fashion. The control side showed no significant metabolic improvement in either area. Follow-up to 12 months in all patients is currently ongoing. This is the first trial of in vivo gene therapy for an adult neurodegenerative disorder, and the safety and efficacy profile seen to date suggests that future, more definitive studies are warranted.Molecular Therapy (2006) 13, S280–S281; doi: 10.1016/j.ymthe.2006.08.807 [ABSTRACT FROM AUTHOR]