Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone.
There are currently no approved antifibrotic therapies for liver cirrhosis. We used vitamin A-coupled liposomes to deliver small interfering RNA (siRNA) against gp46, the rat homolog of human heat shock protein 47, to hepatic stellate cells. Our approach exploits the key roles of these cells in both fibrogenesis as well as uptake and storage of vitamin A. Five treatments with the siRNA-bearing vitamin A-coupled liposomes almost completely resolved liver fibrosis and prolonged survival in rats with otherwise lethal dimethylnitrosamine-induced liver cirrhosis in a dose- and duration-dependent manner. Rescue was not related to off-target effects or associated with recruitment of innate immunity. Receptor-specific siRNA delivery was similarly effective in suppressing collagen secretion and treating fibrosis induced by CCl(4) or bile duct ligation. The efficacy of the approach using both acute and chronic models of liver fibrosis suggests its therapeutic potential for reversing human liver cirrhosis.
Sato
Yasushi
Y
Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, 060-8543, Japan.
Murase
Kazuyuki
K
Kato
Junji
J
Kobune
Masayoshi
M
Sato
Tsutomu
T
Kawano
Yutaka
Y
Takimoto
Rishu
R
Takada
Kouichi
K
Miyanishi
Koji
K
Matsunaga
Takuya
T
Takayama
Tetsuji
T
Niitsu
Yoshiro
Y
D000818:Animals; D003094:Collagen / Q000235:genetics*; D004337:Drug Carriers / Q000737:chemistry; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D008103:Liver Cirrhosis / Q000235:genetics / Q000628:therapy*; D018832:Molecular Chaperones / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D016896:Treatment Outcome; D014801:Vitamin A / Q000008:administration & dosage*
D004337:Drug Carriers; D008081:Liposomes; D018832:Molecular Chaperones; D034741:RNA, Small Interfering; D014801:Vitamin A; D003094:Collagen