Fast track — ArticlesGene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial
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 GDNF4 that improved dopaminergic activity in aged monkeys5 and also protected dopamine neurons in animal models of Parkinson's disease.6, 7, 8, 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.
Section snippets
Patients
We did a double blind, randomised, multicentre trial. Men and women who were of any ethnic group, were 35–75 years of age, and had idiopathic Parkinson's disease according to the UK Brain Bank Criteria20 with disease duration of at least 5 years were eligible. Inclusion criteria were a good response to levodopa in the opinion of the treating investigator and levodopa-induced motor complications that could not be satisfactorily controlled with medical therapy; at least 2 h per day of off time
Results
Between December, 2006, and November, 2008, 58 eligible patients from nine sites in the USA participated in the trial (figure 1). 38 patients were assigned to AAV2-neurturin and 20 to sham surgery. There were no significant differences in demographics and baseline characteristics between groups (table 1). 53 patients completed all scheduled visits of the 12-month study (figure 1).
Table 2 shows the results of the primary and secondary outcome measures at 12 months. UPDRS part 3 score was 38·65
Discussion
We report the results of the first double-blind, controlled phase 2 trial of a gene therapy for Parkinson's disease (panel). Patients who received AAV2-neurturin did not show significant improvement with respect to the primary outcome measure at 12 months compared with those who received sham surgery. At 18 months, AAV2-neurturin treatment was associated with modest, but significant, benefits in the primary outcome compared with controls, but the sample size was small. Several secondary
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