RNA interference targeting Fas protects mice from fulminant hepatitis.
RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. However, its potential to treat or prevent disease remains unproven. Fas-mediated apoptosis is implicated in a broad spectrum of liver diseases, where inhibiting hepatocyte death is life-saving. We investigated the in vivo silencing effect of small interfering RNA (siRNA) duplexes targeting the gene Fas (also known as Tnfrsf6), encoding the Fas receptor, to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis. Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels and expression of Fas protein in mouse hepatocytes, and the effects persisted without diminution for 10 days. Hepatocytes isolated from mice treated with Fas siRNA were resistant to apoptosis when exposed to Fas-specific antibody or co-cultured with concanavalin A (ConA)-stimulated hepatic mononuclear cells. Treatment with Fas siRNA 2 days before ConA challenge abrogated hepatocyte necrosis and inflammatory infiltration and markedly reduced serum concentrations of transaminases. Administering Fas siRNA beginning one week after initiating weekly ConA injections protected mice from liver fibrosis. In a more fulminant hepatitis induced by injecting agonistic Fas-specific antibody, 82% of mice treated with siRNA that effectively silenced Fas survived for 10 days of observation, whereas all control mice died within 3 days. Silencing Fas expression with RNAi holds therapeutic promise to prevent liver injury by protecting hepatocytes from cytotoxicity.
Song
Erwei
E
Center for Blood Research and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Lee
Sang-Kyung
SK
Wang
Jie
J
Ince
Nedim
N
Ouyang
Nengtai
N
Min
Jun
J
Chen
Jisheng
J
Shankar
Premlata
P
Lieberman
Judy
J
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D004195:Disease Models, Animal; D020868:Gene Silencing; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy*; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D009336:Necrosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
D034741:RNA, Small Interfering; D019014:fas Receptor; D003208:Concanavalin A