title: Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial.
abstract: OBJECTIVE
  A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra.
  
  
  METHODS
  We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state.
  
  
  RESULTS
  Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin.
  
  
  CONCLUSIONS
  AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin.
authors.affiliation: Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY.
authors.forename: C
authors.initials: C
authors.lastname: Warren Olanow
authors.affiliation: RTBioconsultants, San Diego, CA.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Bartus
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Baumann
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Factor
authors.affiliation: Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Boulis
authors.affiliation: Department of Neurology, Duke University School of Medicine, Durham, NC.
authors.forename: Mark
authors.initials: M
authors.lastname: Stacy
authors.affiliation: Department of Neurosurgery, Duke University School of Medicine, Durham, NC.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Turner
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA.
authors.forename: William
authors.initials: W
authors.lastname: Marks
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA.
authors.forename: Paul
authors.initials: P
authors.lastname: Larson
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA.
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Starr
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine, Houston, TX.
authors.forename: Richard
authors.initials: R
authors.lastname: Simpson
authors.affiliation: Department of Neurology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Ray
authors.initials: R
authors.lastname: Watts
authors.affiliation: Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Barton
authors.initials: B
authors.lastname: Guthrie
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, CA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Poston
authors.affiliation: Department of Neurosurgery, Stanford University Medical Center, Stanford, CA.
authors.forename: Jaimie M
authors.initials: JM
authors.lastname: Henderson
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Stern
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Baltuch
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Goetz
authors.affiliation: Ceregene, San Diego, CA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Herzog
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kordower
authors.affiliation: Beth Israel-Deaconess Medical Center, Department of Neurosurgery, Boston, MA.
authors.forename: Ron
authors.initials: R
authors.lastname: Alterman
authors.affiliation: Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Lozano
authors.affiliation: Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
mesh_terms: D000368:Aged; D001370:Axonal Transport; D000229:Dependovirus; D004311:Double-Blind Method; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D051101:Neurturin / Q000235:genetics*; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D011699:Putamen / Q000378:metabolism* / Q000503:physiopathology; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: C495053:NRTN protein, human; D051101:Neurturin