Long-term follow-up of a randomized AAV2- GAD gene therapy trial for Parkinson's disease

JCI Insight. 2017 Apr 6;2(7):e90133. doi: 10.1172/jci.insight.90133.


BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and 18F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2-GAD group compared with the sham group continued at 12 months [time effect: F(4,138) = 11.55, P < 0.001; group effect: F(1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-GAD group (P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines (P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2-GAD group (P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2-GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Dependovirus
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Glutamate Decarboxylase / genetics*
  • Humans
  • Male
  • Middle Aged
  • Parkinson Disease / diagnostic imaging
  • Parkinson Disease / therapy*
  • Parvovirinae
  • Positron-Emission Tomography
  • Subthalamic Nucleus / diagnostic imaging
  • Subthalamic Nucleus / physiopathology
  • Treatment Outcome
  • United States


  • Glutamate Decarboxylase

Supplementary concepts

  • Adeno-associated virus-2

Associated data

  • ClinicalTrials.gov/NCT00643890