Resolution of experimental liver fibrosis in mice by targeted delivery of connective tissue growth factor siRNA

Abstract

Resolution of experimental liver fibrosis in mice by targeted delivery of connective tissue growth factor siRNAConnective tissue growth factor (CTGF) promotes liver fibrosis by stimulating collagen production in activated hepatic stellate cells (HSC). Here, we investigated the curative properties of CTGF siRNA delivered to activated HSC in acute or chronic models of CCl4‐induced liver fibrosis. Modified liposomes containing CTGF siRNA were coated with a collagen Type VI receptor‐binding peptide. Balb/c mice received daily injections of CCl4 or oil control for either 3 or 5 weeks. During the last 2 weeks of these regimens, some mice also received concurrent daily injections of CTGF siRNA in targeted liposomes ("CTGF siRNA‐TL") or scrambled CTGF siRNA in targeted liposomes ("CTGF SsiRNA‐TL"). Administration of CCl4 for 3 or 5 weeks resulted in high levels of α‐SMA‐positive cells and deposition of collagen. Whereas this response was unaffected by administration of CTGF SsiRNA‐TL, neither α‐SMA‐positive cells nor collagen deposits were present in CTGF siRNA‐TL‐treated livers. Real‐time PCR showed that the CCl4‐induced mRNA expression of α‐SMA, collagen Type I α1, TGF‐β, or CTGF was restored to baseline values by CTGF siRNA‐TL (p< 0.01) but not by CTGF SsiRNA‐TL. Thus, this targeted liposomal delivery system designed to deliver CTGF siRNA to activated HSC was effective in either preventing or reversing fibrosis even in the continued presence of the fibrotic insult.