Articles AAV2 GAD gene therapy for advanced Parkinson s disease a double blind sham surgery controlled randomised trial Peter 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 Feigin Summary 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 e ect of bilateral delivery of AAV2 GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson s disease Lancet Neurol 2011 10 309 19 Methods Patients aged 30 75 years who had progressive levodopa responsive Parkinson s disease and an overnight o 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 e cacy analysis The primary outcome measure was the 6 month change from baseline in double blind assessment of o medication UPDRS motor scores This trial is registered with ClinicalTrials gov NCT00643890 See Comment page 290 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 e 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 Introduction Neurodegeneration 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 pharmacotherapy often fails to provide adequate symptom relief and sometimes causes disabling complications such as motor fluctuations 1 2 Additional treatment approaches such as deep brain stimulation DBS and pharmacological interventions at sites beyond the nigrostriatal dopaminergic 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 e cacy of gene therapy has yet to be confirmed in a randomised double blind clinical trial 8 In 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 www thelancet com neurology Vol 10 April 2011 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 di culties 12 14 Furthermore this technique necessitates implantation of devices and much e ort to adjust electrical stimulation variables Gene therapy consisting of insertion of the glutamic acid decarboxylase gene GAD into the subthalamic nucleus may o er an alternative therapeutic strategy GAD is the rate limiting enzyme for GABA production and the activity of both GABA e erents to the subthalamic nucleus and its targets within the basal ganglia circuitry are a 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 firing rates and temporarily improved parkinsonian symptoms 15 suggesting that Published Online March 17 2011 DOI 10 1016 S14744422 11 70039 4 These authors contributed equally Wayne State University School of Medicine Parkinson s Disease and Movement Disorders Program Henry Ford West Bloomfield 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 Bloomfield 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 Fort Lee NJ USA C V Sapan PhD Weill Cornell Medical College New York NY USA M G Kaplitt MD and The Feinstein Institute for Medical Research North Shore LIJ Health System Manhasset NY USA A Feigin MD Correspondence to Dr Andrew Feigin The Feinstein Institute for Medical Research North Shore LIJ Health System 350 Community Drive Manhasset NY 11030 USA afeigin nshs edu 309 Articles improvement of GABA transmission within the subthalamic nucleus could be beneficial in Parkinson s disease Similar results in animal models of parkinsonism were achieved with gene transfer of GAD 16 17 This strategy uses an adeno associated viral vector AAV2 to deliver GAD to the subthalamic nucleus to both
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