A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease.
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.
Tuszynski
Mark H
MH
Department of Neurosciences, University of California at San Diego, La Jolla 92093, USA. mtuszynski@ucsd.edu <mtuszynski@ucsd.edu>
Thal
Leon
L
Pay
Mary
M
Salmon
David P
DP
U
Hoi Sang
HS
Bakay
Roy
R
Patel
Piyush
P
Blesch
Armin
A
Vahlsing
H Lee
HL
Ho
Gilbert
G
Tong
Gang
G
Potkin
Steven G
SG
Fallon
James
J
Hansen
Lawrence
L
Mufson
Elliott J
EJ
Kordower
Jeffrey H
JH
Gall
Christine
C
Conner
James
J
D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002799:Cholinergic Fibers / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006652:Histological Techniques; D006801:Humans; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology / Q000601:surgery*
D019788:Fluorodeoxyglucose F18; D020932:Nerve Growth Factor