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Ann Neurol. 2015 Aug;78(2):248-57. doi: 10.1002/ana.24436. Epub 2015 Jun 10.

Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial.

Author information

1
Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY.
2
RTBioconsultants, San Diego, CA.
3
Isis Pharmaceuticals, Carlsbad, CA.
4
Department of Neurology, Emory University School of Medicine, Atlanta, GA.
5
Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA.
6
Department of Neurology, Duke University School of Medicine, Durham, NC.
7
Department of Neurosurgery, Duke University School of Medicine, Durham, NC.
8
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA.
9
Department of Neurology, Baylor College of Medicine, Houston, TX.
10
Department of Neurosurgery, Baylor College of Medicine, Houston, TX.
11
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL.
12
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL.
13
Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, CA.
14
Department of Neurosurgery, Stanford University Medical Center, Stanford, CA.
15
Department of Neurology, University of Pennsylvania, Philadelphia, PA.
16
Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA.
17
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.
18
Ceregene, San Diego, CA.
19
Beth Israel-Deaconess Medical Center, Department of Neurosurgery, Boston, MA.
20
Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
21
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

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.

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.

PMID:
26061140
DOI:
10.1002/ana.24436
[Indexed for MEDLINE]

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