A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease

Michael S. Rafii; Tiffany L. Baumann; Roy A.E. Bakay; Jeffrey M. Ostrove; Joao Siffert; Adam S. Fleisher; Christopher D. Herzog; David Barba; Mary Pay; David P. Salmon; Yaping Chu; Jeffrey H. Kordower; Kathie Bishop; David Keator; Steven Potkin; Raymond T. Bartus

doi:10.1016/j.jalz.2013.09.004

A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease

Michael S. Rafii, Tiffany L. Baumann, Roy A.E. Bakay, Jeffrey M. Ostrove, Joao Siffert, Adam S. Fleisher, Christopher D. Herzog, David Barba, Mary Pay, David P. Salmon, Yaping Chu, Jeffrey H. Kordower, Kathie Bishop, David Keator, Steven Potkin, Raymond T. Bartus

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

167 Scopus citations

Abstract

BACKGROUND: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful.

METHODS: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert.

RESULTS: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity.

CONCLUSIONS: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

Original language	English (US)
Pages (from-to)	571-581
Number of pages	11
Journal	Alzheimer's and Dementia
Volume	10
Issue number	5
DOIs	https://doi.org/10.1016/j.jalz.2013.09.004
State	Published - Sep 1 2014
Externally published	Yes

Keywords

Cholinergic neurons
Gene therapy
Nerve growth factor
Neuroprotection
Neurorestoration
Neurotrophic factors
Nucleus basalis of Meynert
Translational R&D

ASJC Scopus subject areas

Epidemiology
Health Policy
Developmental Neuroscience
Clinical Neurology
Geriatrics and Gerontology
Psychiatry and Mental health
Cellular and Molecular Neuroscience

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10.1016/j.jalz.2013.09.004

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Rafii, M. S., Baumann, T. L., Bakay, R. A. E., Ostrove, J. M., Siffert, J., Fleisher, A. S., Herzog, C. D., Barba, D., Pay, M., Salmon, D. P., Chu, Y., Kordower, J. H., Bishop, K., Keator, D., Potkin, S., & Bartus, R. T. (2014). A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease. Alzheimer's and Dementia, 10(5), 571-581. https://doi.org/10.1016/j.jalz.2013.09.004

Rafii, MS, Baumann, TL, Bakay, RAE, Ostrove, JM, Siffert, J, Fleisher, AS, Herzog, CD, Barba, D, Pay, M, Salmon, DP, Chu, Y, Kordower, JH, Bishop, K, Keator, D, Potkin, S & Bartus, RT 2014, 'A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease', Alzheimer's and Dementia, vol. 10, no. 5, pp. 571-581. https://doi.org/10.1016/j.jalz.2013.09.004

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abstract = "BACKGROUND: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful.METHODS: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert.RESULTS: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity.CONCLUSIONS: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.",

keywords = "Cholinergic neurons, Gene therapy, Nerve growth factor, Neuroprotection, Neurorestoration, Neurotrophic factors, Nucleus basalis of Meynert, Translational R&D",

author = "Rafii, {Michael S.} and Baumann, {Tiffany L.} and Bakay, {Roy A.E.} and Ostrove, {Jeffrey M.} and Joao Siffert and Fleisher, {Adam S.} and Herzog, {Christopher D.} and David Barba and Mary Pay and Salmon, {David P.} and Yaping Chu and Kordower, {Jeffrey H.} and Kathie Bishop and David Keator and Steven Potkin and Bartus, {Raymond T.}",

year = "2014",

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doi = "10.1016/j.jalz.2013.09.004",

language = "English (US)",

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T1 - A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease

AU - Rafii, Michael S.

AU - Baumann, Tiffany L.

AU - Bakay, Roy A.E.

AU - Ostrove, Jeffrey M.

AU - Siffert, Joao

AU - Fleisher, Adam S.

AU - Herzog, Christopher D.

AU - Barba, David

AU - Pay, Mary

AU - Salmon, David P.

AU - Chu, Yaping

AU - Kordower, Jeffrey H.

AU - Bishop, Kathie

AU - Keator, David

AU - Potkin, Steven

AU - Bartus, Raymond T.

PY - 2014/9/1

Y1 - 2014/9/1

N2 - BACKGROUND: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful.METHODS: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert.RESULTS: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity.CONCLUSIONS: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

AB - BACKGROUND: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful.METHODS: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert.RESULTS: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity.CONCLUSIONS: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.

KW - Cholinergic neurons

KW - Gene therapy

KW - Nerve growth factor

KW - Neuroprotection

KW - Neurorestoration

KW - Neurotrophic factors

KW - Nucleus basalis of Meynert

KW - Translational R&D

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SN - 1552-5260

VL - 10

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JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 5

ER -

A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease

Abstract

Keywords

ASJC Scopus subject areas

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