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

doi:10.1016/S1474-4422(10)70254-4

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

Lancet Neurol. 2010 Dec;9(12):1164-1172. doi: 10.1016/S1474-4422(10)70254-4. Epub 2010 Oct 20.

Authors

William J Marks Jr¹, Raymond T Bartus², Joao Siffert², Charles S Davis³, Andres Lozano⁴, Nicholas Boulis⁵, Jerrold Vitek⁶, Mark Stacy⁷, Dennis Turner⁸, Leonard Verhagen⁹, Roy Bakay¹⁰, Raymond Watts¹¹, Barton Guthrie¹², Joseph Jankovic¹³, Richard Simpson¹⁴, Michele Tagliati¹⁵, Ron Alterman¹⁶, Matthew Stern¹⁷, Gordon Baltuch¹⁸, Philip A Starr¹⁹, Paul S Larson¹⁹, Jill L Ostrem¹, John Nutt²⁰, Karl Kieburtz²¹, Jeffrey H Kordower⁹, C Warren Olanow²²

Affiliations

¹ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
² Ceregene, San Diego, CA, USA.
³ CSD Biostatistics, San Diego, CA, USA.
⁴ Department of Neurosurgery, University of Toronto, Toronto, Canada.
⁵ Department of Neurosurgery, Cleveland Clinic, Cleveland, OH, USA.
⁶ Department of Neurology, Cleveland Clinic, Cleveland, OH, USA.
⁷ Department of Neurology, Duke University, Durham, NC, USA.
⁸ Department of Neurosurgery, Duke University, Durham, NC, USA.
⁹ Department of Neurology, Rush Medical University, Chicago, IL, USA.
¹⁰ Department of Neurosurgery, Rush Medical University, Chicago, IL, USA.
¹¹ Department of Neurology, University of Alabama, Birmingham, AL, USA.
¹² Department of Neurosurgery, University of Alabama, Birmingham, AL, USA.
¹³ Department of Neurology, Baylor University, Houston, TX, USA.
¹⁴ Department of Neurosurgery, Baylor University, Houston, TX, USA.
¹⁵ Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
¹⁶ Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY, USA.
¹⁷ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
¹⁸ Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
¹⁹ Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
²⁰ Department of Neurology, University of Oregon, Portland, OR, USA.
²¹ Department of Neurology, University of Rochester, Rochester, NY, USA.
²² Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA; Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA; Institute of Neurology, IRCCS San Raffaele Pisana, Rome, Italy. Electronic address: [email protected].

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

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.

Publication types

Clinical Trial, Phase II
Multicenter Study
Randomized Controlled Trial

MeSH terms

Adult
Aged
Analysis of Variance
Dependovirus / genetics
Dependovirus / physiology*
Double-Blind Method
Female
Follow-Up Studies
Genetic Therapy / methods*
Humans
Male
Middle Aged
Motor Activity / physiology
Neurturin / genetics*
Neurturin / metabolism
Neurturin / therapeutic use*
Parkinson Disease / genetics
Parkinson Disease / physiopathology
Parkinson Disease / therapy*
Putamen / metabolism
Putamen / physiology
Severity of Illness Index
Time Factors
Treatment Outcome

Substances

NRTN protein, human
Neurturin

Associated data

ClinicalTrials.gov/NCT00400634