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

Autor:	Niethammer M; Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA., Tang CC; Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA., LeWitt PA; 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., Rezai AR; Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio, USA., Leehey MA; Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA., Ojemann SG; Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA., Flaherty AW; Department of Neurology and., Eskandar EN; Department of Neurology and.; Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA., Kostyk SK; Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, Ohio, USA., Sarkar A; Department of Neurosurgery, Geisinger Health System, Danville, Pennsylvania, USA., Siddiqui MS; Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Tatter SB; Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Schwalb JM; Movement Disorder & Comprehensive Epilepsy Centers, Henry Ford Medical Group, West Bloomfield, Michigan, USA., Poston KL; Department of Neurology and Neurological Sciences and.; Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA., Henderson JM; Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA., Kurlan RM; Neurology, The Center for Neurological and Neurodevelopmental Health, Voorhees, New Jersey, USA., Richard IH; Department of Neurology and Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA., Sapan CV; Asana Medical Inc., Miami Lakes, Florida, USA., Eidelberg D; Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA., During MJ; 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., Kaplitt MG; Department of Neurological Surgery, Weill Cornell Medical College, New York, New York, USA., Feigin A; Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2017 Apr 06; Vol. 2 (7), pp. e90133. Date of Electronic Publication: 2017 Apr 06.
DOI:	10.1172/jci.insight.90133
Abstrakt:	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 18 F-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. Competing Interests: 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.
Databáze:	MEDLINE
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