Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce l-dopa

Abstract

A combination of gene transfer and intracerebral grafting may provide a powerful technique for examining the role of discrete substances in the development or functioning of the brain. In the present study, primary fibroblasts obtained from a skin biopsy from inbred Fischer rats were used as donor cells for genetic modification and grafting. When grafted to the striatum of Fischer rats with a prior 6-hydroxydopamine lesion, primary fibroblasts containing a transgene for either tyrosine hydroxylase (TH) or β-galactosidase survived for 10 weeks and continued to express the transgene. TH synthesized by the implanted fibroblasts appeared to convert tyrosine to l-dopa actively, as observed in vitro, and to affect the host brain, as assessed through a behavioral measurement. These results suggest that primary fibroblasts genetically altered to express TH have the capacity to deliver l-dopa locally to the striatum in quantities sufficient to compensate partially for the loss of intrinsic striatal dopaminergic input.