Subthalamic Glutamic Acid Decarboxylase Gene Therapy: Changes in Motor Function and Cortical Metabolism
Physics and Astronomy
Parkinson's disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group time interaction, P<0.001). On FDG PET, the GAD animals exhibited an increase in glucose utilization in the right motor cortex relative to GFP controls (P<0.001). Metabolism in this region correlated with clinical ratings at end point (P<0.01). Histology confirmed GAD expression in treated animals. These findings suggest that STN AAV-GAD is well tolerated and potentially effective in a primate model of PD. The changes in motor cortical glucose utilization observed after gene therapy are consistent with the modulation of metabolic brain networks associated with this disorder.
Journal of Cerebral Blood Flow & Metabolism
M.E. Emborg, M. Carbon, J.E. Holden, M.J. During, Y. Ma, C. Tang, J. Moirano, H. Fitzsimons, B.Z. Roitberg, E. Tuccar, A.D. Roberts, M.G. Kaplitt, and D. Eidelberg. (2007). Subthalamic Glutamic Acid Decarboxylase Gene Therapy: Changes in Motor Function and Cortical Metabolism. Journal of Cerebral Blood Flow & Metabolism, 27, 501-509.
Publisher's Copyright and Source
Copyright © 2007 International Society for Cerebral Blood Flow & Metabolism. Article published by Nature Publishing Group in Journal of Cerebral Blood Flow & Metabolism, volume 27, 2007, pages 501-509. Available online on July 12, 2006: http://doi.org/10.1038/sj.jcbfm.9600364.