Synergistic growth factors enhance rat liver proliferation and enable retroviral gene transfer via a peripheral vein.
OBJECTIVE
Genetic diseases reflecting abnormal hepatocyte function are potentially curable through gene therapy. Retroviral vectors offer the potential for permanent correction of such conditions. These vectors generally require cell division to occur to allow provirus entry into the nucleus, initiated in many experimental protocols by partial hepatectomy. We have explored methods to improve the efficiency of retroviral gene transfer that avoid the need for liver damage.


METHODS
Triiodothyronine (T3) and keratinocyte growth factor (KGF) were used to induce hepatic proliferation in rats. The effects of intraportal and peripheral administration of a modified retrovirus that encoded the Lac Z gene during growth factor-induced liver hyperplasia were analyzed.


RESULTS
T3 initiated hepatocyte proliferation midzonally; after KGF, proliferation was more diffuse. Optimal concentrations of T3 and KGF acted synergistically to induce proliferation in 61% of hepatocytes in the intact liver. This enabled in vivo hepatocyte transduction, leading to gene expression by up to 7.3% of hepatocytes after intraportal retroviral vector administration and 7. 1% after peripheral venous administration.


CONCLUSIONS
T3 and KGF act synergistically to induce hepatocyte proliferation in undamaged liver. The liver can be simply transduced with integrating vectors via the peripheral venous system during a wave of growth factor-induced proliferation.
Forbes
S J
SJ
Liver Group Laboratory, Imperial College School of Medicine, London, England.
Themis
M
M
Alison
M R
MR
Sarosi
I
I
Coutelle
C
C
Hodgson
H J
HJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D007275:Injections, Intravenous; D008099:Liver / Q000166:cytology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012190:Retroviridae / Q000235:genetics*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D014161:Transduction, Genetic / Q000502:physiology; D014284:Triiodothyronine / Q000494:pharmacology*
C496455:Fgf7 protein, rat; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D014284:Triiodothyronine; C061134:dioctadecylamidoglycylspermine; D051523:Fibroblast Growth Factor 7; D013096:Spermine; D005346:Fibroblast Growth Factors; D005998:Glycine