AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trialIntroductionMethodsPatientsRandomisation and maskingProceduresStatistical analysisRole of the funding sourceResultsDiscussionAcknowledgmentsReferenceswww.thelancet.com/neurology Vol 10 April 2011 309ArticlesAAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trialPeter A LeWitt, Ali R Rezai, Maureen A Leehey, Steven G Ojemann, Alice W Flaherty, Emad N Eskandar, Sandra K Kostyk, Karen Thomas, Atom Sarkar, Mustafa S Siddiqui, Stephen B Tatter, Jason M Schwalb, Kathleen L Poston, Jaimie M Henderson, Roger M Kurlan, Irene H Richard, Lori Van Meter, Christine V Sapan, Matthew J During*, Michael G Kaplitt*, Andrew FeiginSummary 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 eff ect 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 unifi ed 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 predefi ned target zone led to exclusion of patients before unmasking for the effi cacy 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 signifi cantly 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 effi cacy 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.IntroductionNeurodegeneration of dopaminergic neurons underlies the motor manifestations of Parkinson’s disease. When mild, Parkinson’s disease is generally well controlled by drugs; however, as the disease progresses, pharmacothera-py often fails to provide adequate symptom relief and sometimes causes disabling complications, such as motor fl uctuations.1,2 Additional treatment approaches, such as deep brain stimulation (DBS) and pharmacological interventions at sites beyond the nigrostriatal dopa-minergic pathway have been used to manage problems of advanced Parkinson’s disease.3 In vivo gene therapy is a new approach. Despite promising results in animal models of parkinsonism and in several open-label clinical investigations,4–7 the effi cacy of gene therapy has yet to be confi rmed in a randomised double-blind clinical trial.8In Parkinson’s disease, loss of nigrostriatal dopaminergic neurons alters striato-pallidal circuitry such that decreased GABA input to the subthalamic nucleus renders this structure disinhibited.9 Treatments that diminish or modulate the activity of the subthalamic nucleus, such as subthalamotomy and DBS, can help with some parkinsonian symptoms.10,11 Like dopaminergic treatment, however, DBS can fail to improve some parkinsonian features such as freezing of gait, imbalance, dysphagia, cognitive and psychiatric problems, and speech diffi -culties.12–14 Furthermore, this technique necessitates implantation of devices and much eff ort to adjust electrical stimulation variables.Gene therapy consisting of insertion of the glutamic acid decarboxylase gene (GAD) into the subthalamic nucleus may off er an alternative therapeutic strategy. GAD is the rate-limiting enzyme for GABA production, and the activity of both GABA eff erents to the subthalamic nucleus and its targets within the basal ganglia circuitry are aff ected in Parkinson’s disease. During DBS surgery in patients with this disease, an infusion of the GABAergic agonist muscimol into the subthalamic nucleus suppressed its neuronal fi ring rates and temporarily improved parkinsonian symptoms,15 suggesting that Lancet Neurol 2011; 10: 309–19Published OnlineMarch 17, 2011DOI:10.1016/S1474-4422(11)70039-4See Comment page 290*These authors contributed equallyWayne State University School of Medicine, Parkinson’s Disease and Movement Disorders Program, Henry Ford West Bloomfi eld Hospital, MI, USA (Prof P A LeWitt MD); Ohio State University College of Medicine, Columbus, OH, USA (Prof A R Rezai MD, S K Kostyk MD, K Thomas DO, A Sarkar MD, Prof M J During MD); University of Colorado School of Medicine, Aurora, CO, USA (Prof M A Leehey MD, S G Ojemann MD); Massachusetts General Hospital, Boston, MA, USA (A W Flaherty MD, E N Eskandar MD); Wake Forest University School of Medicine, Winston-Salem, NC, USA (M S Siddiqui MD, Prof S B Tatter MD); Henry Ford Health System, West Bloomfi eld Charter Township, MI, USA (J M Schwalb MD); Stanford University School of Medicine, Stanford, CA, USA (K L Poston MD, J M Henderson MD); University of Rochester School of Medicine, Rochester, NY, USA (Prof R M Kurlan MD, I H Richard MD); PharmaNet Development Group, Princeton, NJ, USA (L Van Meter MS); Neurologix Inc,
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