Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial
C. Warren Olanow MD
Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY
Search for more papers by this authorCorresponding Author
Raymond T. Bartus PhD
RTBioconsultants, San Diego, CA
Address correspondence to Dr Bartus, President, RTBioconsultants, 5442 Shannon Ridge Lane, San Diego, CA 92130. E-mail: [email protected]Search for more papers by this authorStewart Factor DO
Department of Neurology, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorNicholas Boulis MD
Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorMark Stacy MD
Department of Neurology, Duke University School of Medicine, Durham, NC
Search for more papers by this authorDennis A. Turner MD
Department of Neurosurgery, Duke University School of Medicine, Durham, NC
Search for more papers by this authorWilliam Marks MD
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorPaul Larson MD
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorPhillip A. Starr MD, PhD
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorJoseph Jankovic MD
Department of Neurology, Baylor College of Medicine, Houston, TX
Search for more papers by this authorRichard Simpson MD
Department of Neurosurgery, Baylor College of Medicine, Houston, TX
Search for more papers by this authorRay Watts MD
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL
Search for more papers by this authorBarton Guthrie MD
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL
Search for more papers by this authorKathleen Poston MD
Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, CA
Search for more papers by this authorJaimie M. Henderson MD
Department of Neurosurgery, Stanford University Medical Center, Stanford, CA
Search for more papers by this authorMatthew Stern MD
Department of Neurology, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorGordon Baltuch MD
Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorChristopher G. Goetz MD
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL
Search for more papers by this authorJeffrey H. Kordower PhD
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL
Search for more papers by this authorRon Alterman MD
Beth Israel–Deaconess Medical Center, Department of Neurosurgery, Boston, MA
Search for more papers by this authorAndres M. Lozano MD, PhD
Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
Search for more papers by this authorAnthony E. Lang MD
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Search for more papers by this authorC. Warren Olanow MD
Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY
Search for more papers by this authorCorresponding Author
Raymond T. Bartus PhD
RTBioconsultants, San Diego, CA
Address correspondence to Dr Bartus, President, RTBioconsultants, 5442 Shannon Ridge Lane, San Diego, CA 92130. E-mail: [email protected]Search for more papers by this authorStewart Factor DO
Department of Neurology, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorNicholas Boulis MD
Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA
Search for more papers by this authorMark Stacy MD
Department of Neurology, Duke University School of Medicine, Durham, NC
Search for more papers by this authorDennis A. Turner MD
Department of Neurosurgery, Duke University School of Medicine, Durham, NC
Search for more papers by this authorWilliam Marks MD
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorPaul Larson MD
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorPhillip A. Starr MD, PhD
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA
Search for more papers by this authorJoseph Jankovic MD
Department of Neurology, Baylor College of Medicine, Houston, TX
Search for more papers by this authorRichard Simpson MD
Department of Neurosurgery, Baylor College of Medicine, Houston, TX
Search for more papers by this authorRay Watts MD
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL
Search for more papers by this authorBarton Guthrie MD
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL
Search for more papers by this authorKathleen Poston MD
Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, CA
Search for more papers by this authorJaimie M. Henderson MD
Department of Neurosurgery, Stanford University Medical Center, Stanford, CA
Search for more papers by this authorMatthew Stern MD
Department of Neurology, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorGordon Baltuch MD
Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA
Search for more papers by this authorChristopher G. Goetz MD
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL
Search for more papers by this authorJeffrey H. Kordower PhD
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL
Search for more papers by this authorRon Alterman MD
Beth Israel–Deaconess Medical Center, Department of Neurosurgery, Boston, MA
Search for more papers by this authorAndres M. Lozano MD, PhD
Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
Search for more papers by this authorAnthony E. Lang MD
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Search for more papers by this authorAbstract
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 × 1011 vector genomes) and putamen (1.0 × 1012 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.
Interpretation
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. Ann Neurol 2015;78:248–257
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