Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce L-dopa.
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 beta-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.
Fisher
L J
LJ
Department of Neurosciences, University of California, San Diego, La Jolla 92093-0624.
Jinnah
H A
HA
Kale
L C
LC
Higgins
G A
GA
Gage
F H
FH
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D007980:Levodopa / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012867:Skin / Q000166:cytology; D016038:Skin Transplantation / Q000502:physiology; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D001616:beta-Galactosidase