Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease
Martin Niethammer, … , Michael G. Kaplitt, Andrew Feigin
Martin Niethammer, … , Michael G. Kaplitt, Andrew Feigin
Published April 6, 2017
Citation Information: JCI Insight. 2017;2(7):e90133. https://doi.org/10.1172/jci.insight.90133.
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Clinical Research and Public Health Neuroscience

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

Abstract

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.

Authors

Martin Niethammer, Chris C. Tang, Peter A. LeWitt, Ali R. Rezai, Maureen A. Leehey, Steven G. Ojemann, Alice W. Flaherty, Emad N. Eskandar, Sandra K. Kostyk, Atom Sarkar, Mustafa S. Siddiqui, Stephen B. Tatter, Jason M. Schwalb, Kathleen L. Poston, Jaimie M. Henderson, Roger M. Kurlan, Irene H. Richard, Christine V. Sapan, David Eidelberg, Matthew J. During, Michael G. Kaplitt, Andrew Feigin

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Figure 1

Clinical improvements after gene therapy.

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Clinical improvements after gene therapy. (A) Changes in mean OFF-state ...
(A) Changes in mean OFF-state Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores at baseline and 1, 3, 6, and 12 months in the AAV2-GAD (red, n = 16) and sham (black, n = 21) groups. After surgery, the patients in both groups showed decreased scores over time (time effect: P < 0.001 by 2-way RMANOVA), with greater improvements in the AAV2-GAD treatment group over all follow-up time points (group effect: P < 0.03; 2 × 5 RMANOVA; *P < 0.05, **P < 0.01, ***P < 0.001, post-hoc Bonferroni tests relative to baseline). (B) Changes in the duration of levodopa-induced dyskinesias (LID) (item 32 of the UPDRS) in the AAV2-GAD (red, n = 16) and sham (black, n = 21) groups over the course of the study. There was a significant difference in duration of LID over time between the two groups (interaction effect: P < 0.02, 2 × 5 RMANOVA). (C) Rate of responders and nonresponders at 12 months. A cutpoint of improvement of 9.0 points identified a significantly greater (χ2 = 5.64, P < 0.02) responder rate in the AAV2-GAD group (10 of 16, 62.5%) than in the sham group (5 of 21, 23.8%) at both time points. A cutpoint improvement of 1 hour for diary-based ON time revealed a significant difference between the two groups (χ2 = 3.86, P < 0.05), with a larger percentage in the AAV2-GAD group (10 of 14, 71.4%) categorized as responders than in the sham group (7 of 19, 36.8%). Two subjects each in the AAV2-GAD and sham groups were missing 12-month diary data and were omitted from this analysis.