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

Clinical Trial

. 2010 Dec;9(12):1164-1172.

doi: 10.1016/S1474-4422(10)70254-4. Epub 2010 Oct 20.

Raymond T Bartus 2, Joao Siffert 2, Charles S Davis 3, Andres Lozano 4, Nicholas Boulis 5, Jerrold Vitek 6, Mark Stacy 7, Dennis Turner 8, Leonard Verhagen 9, Roy Bakay 10, Raymond Watts 11, Barton Guthrie 12, Joseph Jankovic 13, Richard Simpson 14, Michele Tagliati 15, Ron Alterman 16, Matthew Stern 17, Gordon Baltuch 18, Philip A Starr 19, Paul S Larson 19, Jill L Ostrem 1, John Nutt 20, Karl Kieburtz 21, Jeffrey H Kordower 9, C Warren Olanow 22

Affiliations

PMID: 20970382
DOI: 10.1016/S1474-4422(10)70254-4

Clinical Trial

William J Marks Jr et al. Lancet Neurol. 2010 Dec.

Abstract

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.

PubMed Disclaimer

Comment in

Gene therapy for Parkinson's disease: do we have the cure?
Benabid AL. Benabid AL. Lancet Neurol. 2010 Dec;9(12):1142-1143. doi: 10.1016/S1474-4422(10)70256-8. Lancet Neurol. 2010. PMID: 21087733 No abstract available.
Of monkeys and men: analysis of the phase 2 double-blind, sham-surgery controlled, randomized trial of AAV2-neurturin gene therapy for Parkinson's disease.
Huddleston DE, Factor SA. Huddleston DE, et al. Curr Neurol Neurosci Rep. 2011 Aug;11(4):345-8. doi: 10.1007/s11910-011-0206-y. Curr Neurol Neurosci Rep. 2011. PMID: 21505812 No abstract available.

Cited by

A synopsis on the role of tyrosine hydroxylase in Parkinson's disease.
Tabrez S, Jabir NR, Shakil S, Greig NH, Alam Q, Abuzenadah AM, Damanhouri GA, Kamal MA. Tabrez S, et al. CNS Neurol Disord Drug Targets. 2012 Jun 1;11(4):395-409. doi: 10.2174/187152712800792785. CNS Neurol Disord Drug Targets. 2012. PMID: 22483313 Free PMC article. Review.
Controlled Striatal DOPA Production From a Gene Delivery System in a Rodent Model of Parkinson's Disease.
Cederfjäll E, Broom L, Kirik D. Cederfjäll E, et al. Mol Ther. 2015 May;23(5):896-906. doi: 10.1038/mt.2015.8. Epub 2015 Jan 16. Mol Ther. 2015. PMID: 25592335 Free PMC article.
shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson's disease model.
Zharikov AD, Cannon JR, Tapias V, Bai Q, Horowitz MP, Shah V, El Ayadi A, Hastings TG, Greenamyre JT, Burton EA. Zharikov AD, et al. J Clin Invest. 2015 Jul 1;125(7):2721-35. doi: 10.1172/JCI64502. Epub 2015 Jun 15. J Clin Invest. 2015. PMID: 26075822 Free PMC article.
Gene Therapy for Parkinson's Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.
Badin RA, Binley K, Van Camp N, Jan C, Gourlay J, Robert C, Gipchtein P, Fayard A, Stewart H, Ralph GS, Lad Y, Kelleher M, Loader J, Hosomi K, Palfi S, Mitrophanous KA, Hantraye P. Badin RA, et al. Mol Ther Methods Clin Dev. 2019 Jul 16;14:206-216. doi: 10.1016/j.omtm.2019.07.002. eCollection 2019 Sep 13. Mol Ther Methods Clin Dev. 2019. PMID: 31406701 Free PMC article.
Targeted repositioning identifies drugs that increase fibroblast growth factor 20 production and protect against 6-hydroxydopamine-induced nigral cell loss in rats.
Fletcher EJR, Jamieson AD, Williams G, Doherty P, Duty S. Fletcher EJR, et al. Sci Rep. 2019 Jun 6;9(1):8336. doi: 10.1038/s41598-019-44803-1. Sci Rep. 2019. PMID: 31171821 Free PMC article.

Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial - PubMed (original) (raw)