IMPLANTS OF POLYMER-ENCAPSULATED HUMAN NGF-SECRETING CELLS IN THE NONHUMAN PRIMATE - RESCUE AND SPROUTING OF DEGENERATING CHOLINERGIC BASALFOREBRAIN NEURONS

Baby hamster kidney (BHK) cells were genetically modified to secrete h igh levels of human nerve growth factor (BHK-hNGF). Following polymer encapsulation, these cells were implanted into the lateral ventricle o f four cynomolgus monkeys immediately following a unilateral transecti on/aspiration of the fornix. Three control monkeys received identical implants, with the exception that the BHK cells were not genetically m odified to secrete hNGF and thus differed only by the hNGF construct. One monkey received a fornix transection only. All monkeys displayed c omplete transections of the fornix as revealed by a comprehensive loss of acetylcholinesterase-containing fibers within the hippocampus ipsi lateral to the lesion. Control monkeys that were either unimplanted or received BHK-control (non-NGF secreting) cell implants did not differ from each other and displayed extensive losses of choline acetyltrans ferase and p75 NGF receptor (NGFr)-immunoreactive neurons within the m edial septum (MS; 53 and 54%, respectively) and vertical limb of the d iagonal band (VLDB; 21 and 30%, respectively) ipsilateral to the lesio n. In contrast, monkeys receiving implants of BHK-hNGF cells exhibited a only a modest loss of cholinergic neurons within the septum (19 and 20%, respectively) and VLDB (7%). Furthermore, only implants of hNGF- secreting cells induced a dense sprouting of cholinergic fibers within the septum, which ramified against the ependymal lining of the ventri cle adjacent to the transplant site. Examination of the capsules retre ived from monkeys just prior to their death revealed an abundance of c ells that produced detectable levels of hNGF in a sufficient concentra tion to differentiate PC12A cells in culture. These findings support t he use of polymer-encapsulated cell therapy as a potential treatment f or neurodegenerative diseases such as Alzheimer disease where basal fo rebrain degeneration is a consistent pathological feature. Moreover, t his encapsulated xenogeneic system may provide therapeutically effecti ve levels of a number of neurotrophic factors, alone or in combination , to select populations of neurons within the central nervous system. (C) 1994 Wiley-Liss, Inc.