Diane Hoffman

Transplantation of a Polymer-Encapsulated Cell Line Genetically Engineered to Release NGF

The delivery of nerve growth factor (NGF) to the lateral ventricle of a fimbria-fornix-lesioned rat prevents the lesion-induced reduction in choline acetyltransferase (ChAT) expression by medial septal cells. Although delivery has been achieved through neural grafting of genetically engineered cell lines which release NGF, transplanted cells have grown beyond the implantation site and formed tumors. The encapsulation of cells within a permselective polymer capsule prior to transplantation allows cell growth only within the capsule space, while allowing molecular exchange between the host tissue and enclosed cells. Rat fibroblasts from the parent cell line (R208F) or fibroblasts genetically modified to produce NGF (R208N.8) were loaded within a thermoplastic hollow fiber-based capsule. Only the capsules loaded with the genetically engineered cells released measurable amounts of NGF in culture. Adult rats received unilateral aspirative fimbria-fornix lesions, followed by intraventricular implantation of a R208F capsule (n = 6) or a R208N.8 capsule (n = 6). After 2 weeks, rats receiving encapsulated cells showed no undue reaction to the implants. With both cell types, the cells remained viable and confined to the capsule space. R208N.8 capsules released sufficient NGF to prevent the lesion-induced loss of septal ChAT expression, whereas R208F capsules did not. This study suggests that encapsulated genetically engineered cells can provide an efficient means for future applications involving delivery of neurotrophic factors.

NGF released from a polymer matrix prevents loss of ChAT expression in basal forebrain neurons following a fimbria-fornix lesion

Following a unilateral fimbria-fornix lesion, the delivery of nerve growth factor (NGF) to the ipsilateral lateral ventricle of the rat can prevent the lesion-induced loss of choline acetyltransferase (ChAT) expression in the ipsilateral medial septum and vertical diagonal band region. In the present study, the ability of polymer rods to deliver NGF and to prevent a decrease in basal forebrain ChAT expression following a fimbria-fornix lesion was assessed. NGF was loaded into an ethylene vinyl acetate copolymer (EVAc) rod, fabricated by a melt-extrusion process. NGF release was established by the ability of the rods to induce neurite extension from PC12 cells and chick E12 dorsal root ganglia. Unilateral aspirative lesions of the fimbria-fornix were performed in adult rats, followed by implantation of a polymer rod into the ipsilateral lateral ventricle. Five animals received EVAc rods containing only the carrier molecule bovine serum albumin (BSA), and six received EVAc rods containing both BSA and NGF. After 2 weeks, ChAT-positive cells were counted in the medial septum and vertical diagonal band regions. Rats with NGF-releasing rods displayed ChAT(+) cell counts ipsilateral to the lesion equal to 88% of those on the contralateral side. In contrast, ChAT(+) cell numbers were 42% in animals with rods releasing BSA only (P less than 0.001). No undue reaction to implanted rods was noted. Following a fimbria-fornix lesion, NGF released from polymer matrices effectively prevents a lesion-induced reduction in ChAT expression in basal forebrain neurons.