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


CONCLUSIONS
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.


BACKGROUND
Ceregene and Michael J Fox Foundation for Parkinson's Research.
Marks
William J
WJ
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Bartus
Raymond T
RT
Ceregene, San Diego, CA, USA.
Siffert
Joao
J
Ceregene, San Diego, CA, USA.
Davis
Charles S
CS
CSD Biostatistics, San Diego, CA, USA.
Lozano
Andres
A
Department of Neurosurgery, University of Toronto, Toronto, Canada.
Boulis
Nicholas
N
Department of Neurosurgery, Cleveland Clinic, Cleveland, OH, USA.
Vitek
Jerrold
J
Department of Neurology, Cleveland Clinic, Cleveland, OH, USA.
Stacy
Mark
M
Department of Neurology, Duke University, Durham, NC, USA.
Turner
Dennis
D
Department of Neurosurgery, Duke University, Durham, NC, USA.
Verhagen
Leonard
L
Department of Neurology, Rush Medical University, Chicago, IL, USA.
Bakay
Roy
R
Department of Neurosurgery, Rush Medical University, Chicago, IL, USA.
Watts
Raymond
R
Department of Neurology, University of Alabama, Birmingham, AL, USA.
Guthrie
Barton
B
Department of Neurosurgery, University of Alabama, Birmingham, AL, USA.
Jankovic
Joseph
J
Department of Neurology, Baylor University, Houston, TX, USA.
Simpson
Richard
R
Department of Neurosurgery, Baylor University, Houston, TX, USA.
Tagliati
Michele
M
Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
Alterman
Ron
R
Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY, USA.
Stern
Matthew
M
Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
Baltuch
Gordon
G
Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
Starr
Philip A
PA
Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
Larson
Paul S
PS
Department of Neurosurgery, University of California San Francisco, San Francisco, CA, USA.
Ostrem
Jill L
JL
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Nutt
John
J
Department of Neurology, University of Oregon, Portland, OR, USA.
Kieburtz
Karl
K
Department of Neurology, University of Rochester, Rochester, NY, USA.
Kordower
Jeffrey H
JH
Department of Neurology, Rush Medical University, Chicago, IL, USA.
Olanow
C Warren
CW
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: warren.olanow@mssm.edu.
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000229:Dependovirus / Q000235:genetics / Q000502:physiology*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D051101:Neurturin / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D011699:Putamen / Q000378:metabolism / Q000502:physiology; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
C495053:NRTN protein, human; D051101:Neurturin