Basal forebrain cholinergic neuronal degeneration is a prominent component of neuronal loss in AlzheimerUs disease (AD). In rats and primates, infusions of nerve growth factor (NGF) intracerebroventricularly (ICV) prevent injury-induced cholinergic neuronal degeneration. Gene therapy may allow the intraparenchymal delivery NGF to the CNS chronically to prevent the cholinergic neuronal degereration in AD. Our objective is to determine whether neurotrophic factor delivery by gene therapy can prevent long-term basal forebrain cholinergic neuronal degeneration in correlative primate models of AD. Retroviral vectors were used to genetically modify primary autologous primate fibroblasts to produce and secrete NGF or b-galactosidase (controls). These cells were grafted to the basal forebrain region of adult rhesus monkeys after fornix transections for periods of up to eight months to assess their ability to prevent injury-induced cholinergic neuronal degeneration (n=6 NGF recipients and 5 b-gal recipients). NGF-transduced cells secreted 13.210.7 (SEM) ng NGF/106 cells/hr in vitro; control cells produced no detectable NGF. After one month in vivo, NGF-secreting cells prevented the degeneration of 67.8 18.4% of cholinergic neurons as assessed by low-affinity neurotrophin receptor (p75) immunocytochemistry, whereas only 27.215.8% of neurons remained detectable among b-gal graft recipients (p,0.05). After 8 months, recipients of NGF-secreting grafts still showed a persistence of 70.4% of neurons. NGF ELISA of grafts after 8 months in vivo showed production of 24.4 ng NGF/gm tissue, whereas no NGF was detected in control grafts. No adverse morphological or functional effects of grafts on the host were detected. We conclude that NGF delivery by gene therapy can prevent cholinergic neuronal degeneration for extended periods in vivo and may be useful in treating the cholinergic component of neuronal loss in AD. *KEY*AlzheimerUs disease, Nerve growth factor, Neurotrophins, Aging, Primate, Rhesus monkey
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