Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: rescue and sprouting of degenerating cholinergic basal forebrain neurons.
Baby hamster kidney (BHK) cells were genetically modified to secrete high levels of human nerve growth factor (BHK-hNGF). Following polymer encapsulation, these cells were implanted into the lateral ventricle of four cynomolgus monkeys immediately following a unilateral transection/aspiration of the fornix. Three control monkeys received identical implants, with the exception that the BHK cells were not genetically modified to secrete hNGF and thus differed only by the hNGF construct. One monkey received a fornix transection only. All monkeys displayed complete transections of the fornix as revealed by a comprehensive loss of acetylcholinesterase-containing fibers within the hippocampus ipsilateral 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 acetyltransferase and p75 NGF receptor (NGFr)-immunoreactive neurons within the medial septum (MS; 53 and 54%, respectively) and vertical limb of the diagonal band (VLDB; 21 and 30%, respectively) ipsilateral to the lesion. 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 ventricle adjacent to the transplant site. Examination of the capsules retreived from monkeys just prior to their death revealed an abundance of cells that produced detectable levels of hNGF in a sufficient concentration to differentiate PC12A cells in culture. These findings support the use of polymer-encapsulated cell therapy as a potential treatment for neurodegenerative diseases such as Alzheimer disease where basal forebrain degeneration is a consistent pathological feature. Moreover, this encapsulated xenogeneic system may provide therapeutically effective levels of a number of neurotrophic factors, alone or in combination, to select populations of neurons within the central nervous system.
Emerich
D F
DF
CytoTherapeutics, Inc., Providence, Rhode Island 02906.
Winn
S R
SR
Harper
J
J
Hammang
J P
JP
Baetge
E E
EE
Kordower
J H
JH
D000109:Acetylcholine / Q000502:physiology*; D000180:Acrylic Resins; D000818:Animals; D001704:Biopolymers; D002460:Cell Line; D006224:Cricetinae; D004339:Drug Compounding; D005260:Female; D006801:Humans; D008252:Macaca fascicularis / Q000033:anatomy & histology*; D008297:Male; D009410:Nerve Degeneration / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism*; D011143:Polyvinyl Chloride; D016548:Prosencephalon / Q000166:cytology / Q000502:physiology*; D019736:Prostheses and Implants
D000180:Acrylic Resins; D001704:Biopolymers; D009414:Nerve Growth Factors; C086656:polyacrylonitrile-polyvinylchloride; D011143:Polyvinyl Chloride; D000109:Acetylcholine