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

William J. Marks; Jill L. Ostrem; Leonard Verhagen; Philip A. Starr; Paul S. Larson; Roy AE Bakay; Robin Taylor; Deborah A. Cahn-Weiner; A. Jon Stoessl; C. Warren Olanow; Raymond T. Bartus

doi:10.1016/S1474-4422(08)70065-6

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

William J. Marks^*, Jill L. Ostrem, Leonard Verhagen, Philip A. Starr, Paul S. Larson, Roy AE Bakay, Robin Taylor, Deborah A. Cahn-Weiner, A. Jon Stoessl, C. Warren Olanow, Raymond T. Bartus

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

525 Scopus citations

Abstract

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 1·3×10¹¹ vector genomes (vg)/patient, and the next six patients received 5·4×10¹¹ vg/patient. This trial is registered with ClinicalTrials.gov, number NCT00252850. Findings: 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). ¹⁸F-levodopa-uptake PET did not change after treatment with either dose of CERE-120. Interpretation: 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. Funding: Ceregene; Michael J Fox Foundation for Parkinson's Research.

Original language	English (US)
Pages (from-to)	400-408
Number of pages	9
Journal	The Lancet Neurology
Volume	7
Issue number	5
DOIs	https://doi.org/10.1016/S1474-4422(08)70065-6
State	Published - May 2008

Funding

We thank: Tiffany Baumann and Dan Lee for operational support during the trial; Kathie Bishop for help with data management, statistical analyses, preparation of figures, and valuable comments on drafts of the manuscript; Chris Herzog, Eve Taylor, and Joao Siffert for assistance with preparation of the manuscript; Mehdi Gasmi for leading the team that constructed and did the initial characterisation of CERE-120; Mark Tuszynski for suggestions during the planning of this study; and Jeffrey Kordower for valuable advice about targeting of the nigrostriatal system. The trial was funded by Ceregene. Additional funding was provided by the Michael J Fox Foundation for Parkinson's Research through a competitive research grant to RTB.

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10.1016/S1474-4422(08)70065-6

Cite this

Marks, W. J., Ostrem, J. L., Verhagen, L., Starr, P. A., Larson, P. S., Bakay, R. AE., Taylor, R., Cahn-Weiner, D. A., Stoessl, A. J., Olanow, C. W., & Bartus, R. T. (2008). 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. The Lancet Neurology, 7(5), 400-408. https://doi.org/10.1016/S1474-4422(08)70065-6

@article{2451e64bea614f02af95ac295d137b0d,

title = "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",

abstract = "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 1·3×1011 vector genomes (vg)/patient, and the next six patients received 5·4×1011 vg/patient. This trial is registered with ClinicalTrials.gov, number NCT00252850. Findings: 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). 18F-levodopa-uptake PET did not change after treatment with either dose of CERE-120. Interpretation: 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. Funding: Ceregene; Michael J Fox Foundation for Parkinson's Research.",

author = "Marks, {William J.} and Ostrem, {Jill L.} and Leonard Verhagen and Starr, {Philip A.} and Larson, {Paul S.} and Bakay, {Roy AE} and Robin Taylor and Cahn-Weiner, {Deborah A.} and Stoessl, {A. Jon} and Olanow, {C. Warren} and Bartus, {Raymond T.}",

note = "Funding Information: We thank: Tiffany Baumann and Dan Lee for operational support during the trial; Kathie Bishop for help with data management, statistical analyses, preparation of figures, and valuable comments on drafts of the manuscript; Chris Herzog, Eve Taylor, and Joao Siffert for assistance with preparation of the manuscript; Mehdi Gasmi for leading the team that constructed and did the initial characterisation of CERE-120; Mark Tuszynski for suggestions during the planning of this study; and Jeffrey Kordower for valuable advice about targeting of the nigrostriatal system. The trial was funded by Ceregene. Additional funding was provided by the Michael J Fox Foundation for Parkinson's Research through a competitive research grant to RTB.",

year = "2008",

month = may,

doi = "10.1016/S1474-4422(08)70065-6",

language = "English (US)",

volume = "7",

pages = "400--408",

journal = "The Lancet Neurology",

issn = "1474-4422",

publisher = "Elsevier Ltd",

number = "5",

}

Marks, WJ, Ostrem, JL, Verhagen, L, Starr, PA, Larson, PS, Bakay, RAE, Taylor, R, Cahn-Weiner, DA, Stoessl, AJ, Olanow, CW & Bartus, RT 2008, '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', The Lancet Neurology, vol. 7, no. 5, pp. 400-408. https://doi.org/10.1016/S1474-4422(08)70065-6

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. / Marks, William J.; Ostrem, Jill L.; Verhagen, Leonard et al.
In: The Lancet Neurology, Vol. 7, No. 5, 05.2008, p. 400-408.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson's disease

T2 - an open-label, phase I trial

AU - Marks, William J.

AU - Ostrem, Jill L.

AU - Verhagen, Leonard

AU - Starr, Philip A.

AU - Larson, Paul S.

AU - Bakay, Roy AE

AU - Taylor, Robin

AU - Cahn-Weiner, Deborah A.

AU - Stoessl, A. Jon

AU - Olanow, C. Warren

AU - Bartus, Raymond T.

N1 - Funding Information: We thank: Tiffany Baumann and Dan Lee for operational support during the trial; Kathie Bishop for help with data management, statistical analyses, preparation of figures, and valuable comments on drafts of the manuscript; Chris Herzog, Eve Taylor, and Joao Siffert for assistance with preparation of the manuscript; Mehdi Gasmi for leading the team that constructed and did the initial characterisation of CERE-120; Mark Tuszynski for suggestions during the planning of this study; and Jeffrey Kordower for valuable advice about targeting of the nigrostriatal system. The trial was funded by Ceregene. Additional funding was provided by the Michael J Fox Foundation for Parkinson's Research through a competitive research grant to RTB.

PY - 2008/5

Y1 - 2008/5

N2 - 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 1·3×1011 vector genomes (vg)/patient, and the next six patients received 5·4×1011 vg/patient. This trial is registered with ClinicalTrials.gov, number NCT00252850. Findings: 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). 18F-levodopa-uptake PET did not change after treatment with either dose of CERE-120. Interpretation: 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. Funding: Ceregene; Michael J Fox Foundation for Parkinson's Research.

AB - 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 1·3×1011 vector genomes (vg)/patient, and the next six patients received 5·4×1011 vg/patient. This trial is registered with ClinicalTrials.gov, number NCT00252850. Findings: 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). 18F-levodopa-uptake PET did not change after treatment with either dose of CERE-120. Interpretation: 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. Funding: Ceregene; Michael J Fox Foundation for Parkinson's Research.

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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

Abstract

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UN SDGs

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