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

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

Niethammer M¹, Tang CC¹, LeWitt PA², Rezai AR³, Leehey MA⁴, Ojemann SG⁴, Flaherty AW⁵, Eskandar EN⁶, Kostyk SK³, Sarkar A⁷, Siddiqui MS⁸, Tatter SB⁸, Schwalb JM⁹, Poston KL¹⁰, Henderson JM¹¹, Kurlan RM¹², Richard IH¹³, Sapan CV¹⁴, Eidelberg D¹, During MJ¹⁵, Kaplitt MG¹⁶, Feigin A¹.

Author information

1: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
2: Parkinson's Disease and Movement Disorders Program, Henry Ford Hospital, West Bloomfield, Michigan, USA; Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA.
3: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio, USA.
4: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
5: Department of Neurology and.
6: Department of Neurology and; Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
7: Department of Neurosurgery, Geisinger Health System, Danville, Pennsylvania, USA.
8: Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
9: Movement Disorder & Comprehensive Epilepsy Centers, Henry Ford Medical Group, West Bloomfield, Michigan, USA.
10: Department of Neurology and Neurological Sciences and; Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
11: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
12: Neurology, The Center for Neurological and Neurodevelopmental Health, Voorhees, New Jersey, USA.
13: Department of Neurology and Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
14: Asana Medical Inc., Miami Lakes, Florida, USA.
15: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio, USA.; Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio, USA.
16: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York, USA.

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.

PMID:: 28405611
PMCID:: PMC5374069
DOI:: 10.1172/jci.insight.90133

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Conflict of interest statement

Conflict of interest: C.C. Tang, P.A. Le Witt, M.A. Leehey, S.G. Ojemann, A.W. Flaherty, S.K. Kostyk, M.S. Siddiqui, S.B. Tatter, J.M. Schwalb, K.L. Poston, I.H. Richard, M.J. During, and M.G. Kaplitt have received funding from funding from Neurologix Inc. M.J. During and M.G. Kaplitt are coinventors on the patent re: Glutamic acid decarboxylase (GAD) based delivery systems (United States Patent No. 7,695,959 B2). D. Eidelberg is a coinventor on the patents re: Markers for use in screening patients for nervous system dysfunction and a method and apparatus for using same (United States Patent No. 5,632,276 and No. 5,873,823). Additional COI information is reported in the supplemental materials.