TY - JOUR
T1 - AAV2-GAD gene therapy for advanced Parkinson's disease
T2 - A double-blind, sham-surgery controlled, randomised trial
AU - LeWitt, Peter A.
AU - Rezai, Ali R.
AU - Leehey, Maureen A.
AU - Ojemann, Steven G.
AU - Flaherty, Alice W.
AU - Eskandar, Emad N.
AU - Kostyk, Sandra K.
AU - Thomas, Karen
AU - Sarkar, Atom
AU - Siddiqui, Mustafa S.
AU - Tatter, Stephen B.
AU - Schwalb, Jason M.
AU - Poston, Kathleen L.
AU - Henderson, Jaimie M.
AU - Kurlan, Roger M.
AU - Richard, Irene H.
AU - Van Meter, Lori
AU - Sapan, Christine V.
AU - During, Matthew J.
AU - Kaplitt, Michael G.
AU - Feigin, Andrew
N1 - Funding Information:
PAL served as a paid speaker for Allergan, Boehringer-Ingelheim, Chelsea Therapeutics, Lundbeck, Novartis, and Ipsen, served as a paid consultant for Boehringer-Ingelheim, GlaxoSmithKline, Impax, Itec, Ipsen, NeuroDerm, Merck, Schering-Plough, and XenoPort; he receives grant funding (grants pending) from Allergan, Boehringer-Ingelheim, Chelsea Therapeutics, The Michael J Fox Foundation for Parkinson's Research, Merz, Novartis, Santhera, and UCB. ARR served as a paid consultant for Autonomic Technologies and Neurologix, received grant funding (grants pending) from Medtronic Neurological, served as a paid speaker for Medtronic Neurological, patents with money to institution from Autonomic Technologies and Intelect Medical, and holds stock options in Surgivision and Autonomic Technologies. MAL received grant funding (grants pending) from Schwartz Biosciences, Molecular Biometrics, IMPAX Pharmaceuticals; served as a paid speaker for Athena Diagnostics, Teva Neurosciences, American Federation of Research, The Movement Disorders Society; and received meeting expenses from Parkinson Study Group. SGO served as a paid consultant for Medtronic. SKK receives salary support from Ohio State University and Chalmers P Wiley VA Medical Center and receives grant funding (grants pending) from National Institute of Health and Huntington's Disease Society of America. KT receives grant funding (grants pending) from Teva, Acadia, UCB, Ipsen, Impax and Chelsea Pharmaceuticals. MSS received travel expenses for research-related meetings, and provisions of writing assistance, medicines, equipment, or administrative support to Wake Forest University School of Medicine from Neurologix. SBT reports grant funding (grants pending) to Wake Forest University School of Medicine from the US Department of Defense, National Institutes of Health and from the National Institutes of Health Neurological Disorders and Stroke. JMH has served on the speakers' bureau for Medtronic. RMK served as a paid consultant for Boehringer-Ingelheim and receives grant funding (grants pending) from Kyowa and Boehringer Ingelheim. IHR reports grant funding (grants pending) to University of Rochester School of Medicine from Eli Lilly and Novartis, and served as a paid speaker for Teva Pharmaceuticals. LVM, an employee of PharmaNet Development Group, Princeton, NJ, USA, served as the study biostatistician under contract from Neurologix. CVS is a paid employee of and holds stock options in Neurologix. MJD is co-founder of, paid consultant for, and holds stock options in Neurologix, and is a co-author on issued patent related to the AAV-GAD product. MGK is cofounder of, paid consultant for, receives grant funding (grants pending) from and holds stock options in Neurologix, patents with financial gain to Rockefeller University and Weill Cornell Medical College, royalties to Weill Cornell Medical College from Neurologix, Ceregene and Genzyme. AF served as a paid consultant for Rexahn and Alnylam Pharmaceuticals, provided expert testimony for medico-legal cases; receives grant funding (grants pending) from National Institutes of Health, The Dana Foundation, Thomas Hartman Foundation for Parkinson's Research, Huntington's Disease Society of America; and has served on the speakers' bureau for Teva Pharmaceuticals and Allergan. The other authors declare that they have no conflicts of interest.
PY - 2011/4
Y1 - 2011/4
N2 - Background: Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-. GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease. Methods: Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890. Findings: Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-. GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-. GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-. GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-. GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-. GAD group vs two in the sham group) and nausea (six vs two). Interpretation: The efficacy and safety of bilateral infusion of AAV2-. GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders. Funding: Neurologix.
AB - Background: Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-. GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease. Methods: Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890. Findings: Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-. GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-. GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-. GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-. GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-. GAD group vs two in the sham group) and nausea (six vs two). Interpretation: The efficacy and safety of bilateral infusion of AAV2-. GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders. Funding: Neurologix.
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U2 - 10.1016/S1474-4422(11)70039-4
DO - 10.1016/S1474-4422(11)70039-4
M3 - Article
C2 - 21419704
AN - SCOPUS:79952740079
SN - 1474-4422
VL - 10
SP - 309
EP - 319
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 4
ER -