Biliary administration of naked DNA encoding Fas-Fc protein prevents acute liver failure in mice.
Acute liver failure (ALF) of infectious origin results from massive Fas-mediated hepatocyte apoptosis. To cure Fas-induced ALF in mice, we have designed a noninvasive procedure for intrahepatic transfer of a plasmid that encodes a molecule inhibiting Fas-Fas ligand interaction. For that purpose, naked pDNA encoding green fluorescent protein (GFP) or the Fas-Fc chimeric protein was transferred into mice by the biliary route. Ten percent of hepatocytes expressed GFP. After pFas-Fc transfer, about 40 ng of Fas-Fc protein per milliliter could be detected in sera from day 4 to day 28. Serum recombinant Fas-Fc could neutralize Fas-induced cell death in vitro. Furthermore, pFas-Fc biliary transfer efficiently protected mice against Fas-mediated ALF, because survival rates (p < 0.01), serum transaminase activities (p < 0.05), and histological data (p < 0.02) were improved versus control pTNFR-Fc-transfected mice. In conclusion, naked pDNA encoding Fas-Fc is efficiently expressed by hepatocytes after biliary gene transfer in mice. This method, devoid of virus-related risks, could be considered for the treatment of Fas-mediated ALF in humans.
Poussin
Delphine
D
Laboratoire d'Immunologie, AP-HP, Faculté Cochin, Université Paris V, France.
Malassagne
Benoit
B
Tran Van Nhieu
Jeanne
J
Trébéden
Helene
H
Guéry
Laurence
L
Chéreau
Christiane
C
Soubrane
Olivier
O
Calmus
Yvon
Y
Weill
Bernard
B
Batteux
Frederic
F
D000818:Animals; D001659:Biliary Tract / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins; D008099:Liver / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000517:prevention & control*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000235:genetics; D014170:Transformation, Genetic; D019014:fas Receptor / Q000097:blood / Q000235:genetics*
D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D049452:Green Fluorescent Proteins; D004247:DNA