Subthalamic Glutamic Acid Decarboxylase Gene Therapy: Changes in Motor Function and Cortical Metabolism

Abstract

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 (18)F-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 x 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.

Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease

“…Moreover, significant improvement relative to the 1 month ratings was evident at later time points, suggesting that the treatment response was delayed. This is, in fact, consistent with preclinical studies suggesting that after AAV-mediated gene transfer, maximal production of the gene product is not achieved for several weeks to months (3,5,25,26). These clinical observations along with an absence of radiographic evidence of STN damage at any time point, support the argument against the possibility that the observed metabolic changes were caused by lesioning.…”

“…Similar metabolic changes have been reported after stereotaxic interventions for PD (10,18,23), likely caused by increases in thalamocortical activity subsequent to treatment-mediated reductions in inhibitory GPi/ SNr output. The observed cortical metabolic increases are also consistent with our preclinical study in a primate model of PD (5). Overall, the metabolic changes observed after STN AAV-GAD are consistent with functional alterations within key elements of the cortico-striato-pallidothalamic-cortical (CSPTC) pathways that mediate the motor symptomatology of PD.…”

“…Based on the notion that reducing glutamatergic neurotransmission may reverse the motor deficits of PD by normalizing brain activity within these circuits, we used adenoassociated virus (AAV) to deliver the glutamic acid decarboxylase (GAD) gene directly into STN (3). Preclinical studies using animal models of PD suggest that transfer of the GAD gene into the STN can alter its activity while also increasing the evoked release of GABA in downstream targets (3)(4)(5). However, these effects cannot be directly assessed in human subjects receiving this form of gene therapy for parkinsonism.…”

Advances in Gene Therapy for Movement Disorders

“…47 The effect of rAAV-GAD gene therapy has also been ascertained in macaque monkeys. 48 Neuroprotective and neurorestorative genes. Because neurotrophic factors cannot cross the blood-brain barrier, and because of problems associated with intracerebroventricular delivery of these proteins, gene transfer approaches have been attempted in animal models of PD.…”

Regulatable promoters and gene therapy for Parkinson's disease: Is the only thing to fear, fear itself?

“…The rationale behind this approach is that delivery of the GAD gene to the STN will decrease the well-established over-activity of this nucleus in a manner analogous to what is done with lesions, and with deep brain stimulation. This approach has also reached Phase 1 clinical trials (Kaplit et al, 2007) in spite of negligible efficacy in parkinsonian monkeys (Emborg et al, 2007). Both of these gene therapy approaches are symptomatic in nature and are not anticipated to affect the underlying disease process.…”