Grafting fibroblasts genetically modified to produce L-dopa in a rat model of Parkinson disease.
Rat fibroblasts were infected with a retroviral vector containing the cDNA for rat tyrosine hydroxylase [TH; tyrosine 3-monooxygenase; L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2]. A TH-positive clone was identified by biochemical assay and immunohistochemical staining. When supplemented in vitro with pterin cofactors required for TH activity, these cells produced L-dopa and released it into the cell culture medium. Uninfected control cells and fibroblasts infected with the TH vector were grafted separately to the caudate of rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. Only grafts containing TH-expressing fibroblasts were found to reduce rotational asymmetry. These results have general implications for the application of gene therapy to human neurological disease and specific implications for Parkinson disease.
Wolff
J A
JA
Department of Pediatrics, University of California School of Medicine, La Jolla 92093.
Fisher
L J
LJ
Xu
L
L
Jinnah
H A
HA
Langlais
P J
PJ
Iuvone
P M
PM
O'Malley
K L
KL
Rosenberg
M B
MB
Shimohama
S
S
Friedmann
T
T
D000818:Animals; D002460:Cell Line; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000201:enzymology / Q000637:transplantation; D005822:Genetic Vectors; D007980:Levodopa / Q000378:metabolism*; D008979:Moloney murine leukemia virus / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000601:surgery*; D010957:Plasmids; D051381:Rats; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
D007980:Levodopa; D004247:DNA; D014446:Tyrosine 3-Monooxygenase