A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease

Mark H. Tuszynski; Leon Thal; Mary Pay; David P. Salmon; Hoi Sang U; Roy Bakay; Piyush Patel; Armin Blesch; H. Lee Vahlsing; Gilbert Ho; Gang Tong; Steven G. Potkin; James Fallon; Lawrence Hansen; Elliott J. Mufson; Jeffrey H. Kordower; Christine Gall; James Conner

doi:10.1038/nm1239

A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease

Mark H. Tuszynski, Leon Thal, Mary Pay, David P. Salmon, Hoi Sang U, Roy Bakay, Piyush Patel, Armin Blesch, H. Lee Vahlsing, Gilbert Ho, Gang Tong, Steven G. Potkin, James Fallon, Lawrence Hansen, Elliott J. Mufson, Jeffrey H. Kordower, Christine Gall, James Conner

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Abstract

Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

Original language	English (US)
Pages (from-to)	551-555
Number of pages	5
Journal	Nature Medicine
Volume	11
Issue number	5
DOIs	https://doi.org/10.1038/nm1239
State	Published - May 2005
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Tuszynski, M. H., Thal, L., Pay, M., Salmon, D. P., Sang U, H., Bakay, R., Patel, P., Blesch, A., Vahlsing, H. L., Ho, G., Tong, G., Potkin, S. G., Fallon, J., Hansen, L., Mufson, E. J., Kordower, J. H., Gall, C., & Conner, J. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine, 11(5), 551-555. https://doi.org/10.1038/nm1239

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title = "A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease",

abstract = "Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.",

author = "Tuszynski, {Mark H.} and Leon Thal and Mary Pay and Salmon, {David P.} and {Sang U}, Hoi and Roy Bakay and Piyush Patel and Armin Blesch and Vahlsing, {H. Lee} and Gilbert Ho and Gang Tong and Potkin, {Steven G.} and James Fallon and Lawrence Hansen and Mufson, {Elliott J.} and Kordower, {Jeffrey H.} and Christine Gall and James Conner",

note = "Funding Information: We acknowledge the pioneering work of F. Gage in laying the foundation for this clinical program. We thank B. Hempstead for providing proNGF and antibody, T. Mead for performing immunoelectrophoresis and R. Bartus for helpful advice. Supported by the Shiley Family Foundation and the Institute for the Study of Aging.",

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AU - Kordower, Jeffrey H.

AU - Gall, Christine

AU - Conner, James

N1 - Funding Information: We acknowledge the pioneering work of F. Gage in laying the foundation for this clinical program. We thank B. Hempstead for providing proNGF and antibody, T. Mead for performing immunoelectrophoresis and R. Bartus for helpful advice. Supported by the Shiley Family Foundation and the Institute for the Study of Aging.

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AB - Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.

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A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease

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