Elsevier

The Lancet Neurology

Volume 9, Issue 12, December 2010, Pages 1164-1172
The Lancet Neurology

Fast track — Articles
Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial

https://doi.org/10.1016/S1474-4422(10)70254-4Get rights and content

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 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

References (33)

  • PT Kotzbauer et al.

    Neurturin, a relative of glial-cell-line-derived neurotrophic factor

    Nature

    (1996)
  • CD Herzog et al.

    Striatal delivery of CERE-120, an AAV2 vector encoding human neurturin, enhances activity of the dopaminergic nigrostriatal system in aged monkeys

    Mov Disord

    (2007)
  • BA Horger et al.

    Neurturin exerts potent actions on survival and function of midbrain dopaminergic neurons

    J Neurosci

    (1998)
  • JH Kordower et al.

    Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys

    Ann Neurol

    (2006)
  • SS Gill et al.

    Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease

    Nat Med

    (2003)
  • JT Slevin et al.

    Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor

    J Neurosurg

    (2005)
  • Cited by (536)

    View all citing articles on Scopus
    View full text