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

Abstract

<b>BACKGROUND.</b> 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. <b>METHODS.</b> 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-<i>GAD</i> 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. <b>RESULTS.</b> Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2-<i>GAD</i> group compared with the sham group continued at 12 months [time effect: <i>F</i>(4,138) = 11.55, <i>P</i> < 0.001; group effect: <i>F</i>(1,35) = 5.45, <i>P</i> < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-<i>GAD</i> group (<i>P</i> = 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 (<i>P</i> < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-<i>GAD</i> 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-<i>GAD</i> group (<i>P</i> < 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. <b>CONCLUSION.</b> These findings show that clinical benefits after gene therapy with STN AAV2-<i>GAD</i> in PD patients persist at 12 months. <b>TRIAL REGISTRATION.</b> ClinicalTrials.gov NCT00643890. <b>FUNDING.</b> Neurologix Inc.