IMPLANTS OF POLYMER-ENCAPSULATED GENETICALLY-MODIFIED CELLS RELEASINGGLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR IMPROVE SURVIVAL, GROWTH,AND FUNCTION OF FETAL DOPAMINERGIC GRAFTS

Neural transplantation as an experimental therapy for Parkinsonian pat ients has been shown to be effective in several clinical trials. Furth er benefit, however; may be expected if the grafting is combined with a treatment of neurotrophic factors thus improving the survival and gr owth of grafted embryonic dopaminergic neurons. Continuous trophic sup port may be needed and therefore requires the long-term delivery of ne urotrophic factors 60 the brain. We demonstrate here that the implanta tion of polymer-encapsulated cells genetically engineered to continuou sly secrete glial cell line-derived neurotrophic factor to the adult r at striatum improves dopaminergic graft survival and function. Near co mplete compensation of 6-hydroxydopamine-induced rotation was already achieved within 3 weeks postgrafting in rats that received glial cell line-derived neurotrophic factor-releasing capsules in addition to dop aminergic cell grafts of cultured tissue. Rats without trophic factor supply showed only little recovery at the same time point and sham gra fted rats showed no recovery. The number of tyrosine hydroxylase-immun oreactive cells per graft was increased 2.6-fold in the presence of gl ial cell line-derived neurotrophic factor 6 weeks postgrafting. Simila rly, tyrosine hydroxylase-immunoreactive fibers around the graft were increased by 53%. Moreover, these fibers showed a preferential growth towards the trophic factor-releasing capsule. Taken together, these re sults provide evidence that encapsulated genetically engineered cells are an effective means of long-term trophic factor supply into the adu lt rat brain and that the delivery of glial cell line-derived neurotro phic factor can sustain dopaminergic graft function and survival. (C) 1998 Academic Press.