1164 www.thelancet.com/neurology Vol 9 December 2010 Articles Lancet Neurol 2010; 9: 1164–72 Published Online October 21, 2010 DOI:10.1016/S1474- 4422(10)70254-4 See Reflection and Reaction page 1142 Departments of Neurology (W J Marks Jr MD, J L Ostrem MD) and Neurosurgery (P A Starr MD, P S Larson MD), University of California San Francisco, San Francisco, CA, USA; Ceregene, San Diego, CA, USA (R T Bartus PhD, J Siffert MD); Departments of Neurosurgery (N Boulis MD) and Neurology (J Vitek MD), Cleveland Clinic, Cleveland, OH, USA; Departments of Neurology (M Stacy MD) and Neurosurgery (D Turner MD), Duke University, Durham, NC, USA; Departments of Neurology (L Verhagen MD, J H Kordower PhD) and Neurosurgery (R Bakay MD), Rush Medical University, Chicago, IL, USA; Departments of Neurology (R Watts MD) and Neurosurgery (B Guthrie MD), University of Alabama, Birmingham, AL, USA; Departments of Neurology (J Jankovic MD) and Neurosurgery (R Simpson MD), Baylor University, Houston, TX, USA; Departments of Neurology (M Tagliati MD, C W Olanow MD), Neurosurgery (R Alterman MD), and Neuroscience (C W Olanow), Mount Sinai School of Medicine, New York, NY, USA; Departments of Neurology (M Stern MD) and Neurosurgery (G Baltuch MD), University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, University of Oregon, Portland, OR, USA (J Nutt MD); CSD Biostatistics, San Diego, CA, USA (C S Davis PhD); Department of Neurosurgery, University of Toronto, Toronto, Canada (A Lozano MD); Department of Neurology, University of Rochester, Rochester, NY, USA Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial William J Marks Jr*, Raymond T Bartus*, Joao Siffert, Charles S Davis, Andres Lozano, Nicholas Boulis, Jerrold Vitek, Mark Stacy, Dennis Turner, Leonard Verhagen, Roy Bakay, Raymond Watts, Barton Guthrie, Joseph Jankovic, Richard Simpson, Michele Tagliati, Ron Alterman, Matthew Stern, Gordon Baltuch, Philip A Starr, Paul S Larson, Jill L Ostrem, John Nutt, Karl Kieburtz, Jeffrey H Kordower, C Warren Olanow* Summary Background In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinson’s disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. Methods We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinson’s disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4×10¹¹ vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinson’s disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. Results Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference –0·31 [SE 2·63], 95% CI –5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. Interpretation Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. Funding Ceregene and Michael J Fox Foundation for Parkinson’s Research. Introduction Parkinson’s disease is a common neurodegenerative disorder characterised clinically by bradykinesia, rigidity, tremor, and gait dysfunction, and pathologically by degeneration of dopamine neurons in the substantia nigra pars compacta. Present therapies provide satisfactory disease control for most patients, particularly in the early stages. However, chronic levodopa treatment is associated with motor complications, does not control potentially disabling features such as falling and dementia, and fails to prevent disease progression. 1 Thus, many patients suffer disability despite available medical and surgical treatments. More effective treatments that improve clinical disease control and slow progression are urgently needed. Neurotrophic factors might improve neuronal function and protect against neurodegeneration. Glial-cell-derived neurotrophic factor (GDNF) protects dopamine neurons in in-vitro and animal models of Parkinson’s disease. 2,3 Neurturin is a naturally occurring structural and functional analogue of GDNF 4 that improved dopaminergic activity in aged monkeys 5 and also protected dopamine neurons in animal models of Parkinson’s disease. 6–9 Results from open-label trials have shown benefits of continuous infusion of GDNF into the putamen in patients with advanced Parkinson’s disease. 10,11 However, these results were not confirmed in double-blind studies, 12,13 possibly because the trophic factor was not adequately distributed throughout the target region. 14,15 Gene delivery has the potential to provide diffuse distribution and long-lasting expression of a therapeutic protein in one surgical procedure, and gene delivery of neurturin and GDNF provides long-term histological and behavioural benefits in primate models of Parkinson’s disease. 5,9,16,17 Adeno-associated type-2 (AAV2)-neurturin is a vector that has been genetically engineered to express and secrete the human gene for neurturin. 8 The AAV2 vector does not induce an inflammatory reaction, has been used safely in clinical trials, and provides long-lasting transgene expression. 18 An open-label, 12-month phase 1 trial of bilateral stereotactic intraputaminal injections of AAV2-neurturin in patients with advanced Parkinson’s disease showed that the treatment was safe, well tolerated, and associated with benefits in motor functions. 19 We therefore aimed to assess the safety and efficacy of stereotactic surgery with injections of AAV2-neurturin versus sham surgery in patients with advanced Parkinson’s disease in a double-blind, randomised trial.