Resolution of liver cirrhosis using vitamin A–coupled liposomes to deliver siRNA against a collagen-specific chaperone

Abstract

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.

Targeting liver fibrosis: Strategies for development and validation of antifibrotic therapies

“…67 Alternatively, vitamin A-modified liposomes increased delivery of small interfering RNA (siRNA) directed against the putative collagen-specific chaperone HSP47 to vitamin A-storing HSC, causing a pronounced antifibrotic effect in the CCl 4 and BDL-induced liver fibrosis. 68 Once effective targeted delivery of siRNA to activated HSC is confirmed, the versatility of this platform holds promise, because it permits the silencing of any known profibrogenic gene. Recently, targeting of adenovirus to the PDGF␤ receptor using the receptor binding octapeptide (CSRNLIDC) cloned upstream of a single-chain antibody fragment directed against the adenoviral knob was employed to redirect adenoviral delivery of siRNA from hepatocytes to activated HSC.…”

Special delivery: targeted therapy with small RNAs

“…62 Stellate cells have a central role in organismal vitamin A uptake and storage, but are also responsible for liver fibrosis in response to liver injury. They express a heat shock protein (gp46) that acts as a chaperone for collagen and is needed to secrete and deposit extracellular collagen in fibrotic liver.…”

Nano-sized carriers in gene therapy for peritoneal fibrosisin vivo

“…Liposome nanoparticles consist of phospholipids and cholesterol, which are the main components of the cell membrane, and thus show high biocompatibility [39,51,52]. Liposome nanoparticles have been reported to deliver transgenes to the peritoneal membrane, and demonstrated therapeutic efficacy in a mouse peritoneal fibrosis model [39].…”