Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease: an open-label, phase I trial.
BACKGROUND
There is an urgent need for therapies that slow or reverse the progression of Parkinson's disease (PD). Neurotrophic factors can improve the function of degenerating neurons and protect against further neurodegeneration, and gene transfer might be a means to deliver effectively these factors to the brain. The aim of this study was to assess the safety, tolerability, and potential efficacy of gene delivery of the neurotrophic factor neurturin.


METHODS
In this phase I, open-label clinical trial, 12 patients aged 35-75 years with a diagnosis of PD for at least 5 years in accordance with the UK Brain Bank Criteria received bilateral, stereotactic, intraputaminal injections of adeno-associated virus serotype 2-neurturin (CERE-120). The first six patients received doses of 1.3x10(11) vector genomes (vg)/patient, and the next six patients received 5.4x10(11) vg/patient. This trial is registered with ClinicalTrials.gov, number NCT00252850.


RESULTS
The procedure was well tolerated. Extensive safety monitoring in all patients revealed no clinically significant adverse events at 1 year. Several secondary measures of motor function showed improvement at 1 year; for example, a mean improvement in the off-medication motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) of 14 points (SD 8; p=0.000121 [36% mean increase; p=0.000123]) and a mean increase of 2.3 h (2; 25% group mean increase; p=0.0250) in on time without troublesome dyskinesia were seen. Improvements in several secondary measures were not significant, including the timed walking test in the off condition (p=0.053), the Purdue pegboard test of hand dexterity (p=0.318), the reduction in off time (p=0.105), and the activities of daily living subscore (part II) of the UPDRS (p=0.080). (18)F-levodopa-uptake PET did not change after treatment with either dose of CERE-120.


CONCLUSIONS
The initial data support the safety, tolerability, and potential efficacy of CERE-120 as a possible treatment for PD; however, these results must be viewed as preliminary until data from blinded, controlled clinical trials are available.


BACKGROUND
Ceregene; Michael J Fox Foundation for Parkinson's Research.
Marks
William J
WJ
Department of Neurology, University of California, San Francisco, San Francisco, CA 94143-0138, USA. william.marks@ucsf.edu
Ostrem
Jill L
JL
Verhagen
Leonard
L
Starr
Philip A
PA
Larson
Paul S
PS
Bakay
Roy Ae
RA
Taylor
Robin
R
Cahn-Weiner
Deborah A
DA
Stoessl
A Jon
AJ
Olanow
C Warren
CW
Bartus
Raymond T
RT
D000328:Adult; D000368:Aged; D000229:Dependovirus / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051101:Neurturin / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D011699:Putamen / Q000187:drug effects*
D051101:Neurturin