title: Long-term follow-up of a randomized AAV2-GADgene 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-GADdelivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and18F-fluorodeoxyglucose (FDG) PET imaging.RESULTS.Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2-GADgroup 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-GADgroup (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-GADgroup 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-GADgroup (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-GADin PD patients persist at 12 months.TRIAL REGISTRATION.ClinicalTrials.gov NCT00643890.FUNDING.Neurologix Inc.
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Niethammer
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Chris C
authors.initials: CC
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Peter A
authors.initials: PA
authors.lastname: LeWitt
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: Ali R
authors.initials: AR
authors.lastname: Rezai
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Leehey
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Ojemann
authors.affiliation: Department of Neurology and.
authors.forename: Alice W
authors.initials: AW
authors.lastname: Flaherty
authors.affiliation: Department of Neurology and.|Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Emad N
authors.initials: EN
authors.lastname: Eskandar
authors.affiliation: Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio, USA.
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Kostyk
authors.affiliation: Department of Neurosurgery, Geisinger Health System, Danville, Pennsylvania, USA.
authors.forename: Atom
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Mustafa S
authors.initials: MS
authors.lastname: Siddiqui
authors.affiliation: Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Tatter
authors.affiliation: Movement Disorder & Comprehensive Epilepsy Centers, Henry Ford Medical Group, West Bloomfield, Michigan, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Schwalb
authors.affiliation: Department of Neurology and Neurological Sciences and.|Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Poston
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jaimie M
authors.initials: JM
authors.lastname: Henderson
authors.affiliation: Neurology, The Center for Neurological and Neurodevelopmental Health, Voorhees, New Jersey, USA.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Kurlan
authors.affiliation: Department of Neurology and Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Richard
authors.affiliation: Asana Medical Inc., Miami Lakes, Florida, USA.
authors.forename: Christine V
authors.initials: CV
authors.lastname: Sapan
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Eidelberg
authors.affiliation: 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.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: During
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kaplitt
authors.affiliation: Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feigin
mesh_terms: D000328:Adult; D000368:Aged; D000229:Dependovirus; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000628:therapy*; D019219:Parvovirinae; D049268:Positron-Emission Tomography; D020531:Subthalamic Nucleus / Q000000981:diagnostic imaging / Q000503:physiopathology; D016896:Treatment Outcome; D014481:United States
chemical_list: D005968:Glutamate Decarboxylase