BACKGROUND/AIMS: RNA interference has considerable therapeutic potential, particularly for anti-viral therapy. We previously reported that hepatitis C virus (HCV)-directed small interfering RNA (siRNA; siE) efficiently inhibits HCV replication, using HCV replicon cells. To employ the siRNA as a therapeutic strategy, we attempted in vivo silencing of intrahepatic HCV gene expression by siE using a novel cationic liposome. METHODS: The liposomes consisted of conjugated lactose residues, based on the speculation that lactose residues would effectively deliver siRNA to the liver via a liver specific receptor. The lactosylated cationic liposome 5 (CL-LA5) that contained the most lactose residues introduced the most siRNA into a human hepatoma cell line, which then inhibited replication of HCV replicons. RESULTS: In mice, the siRNA/CL-LA5 complexes accumulated primarily in the liver and were widespread throughout the hepatic parenchymal cells. Moreover, siE/CL-LA5 specifically and dose-dependently suppressed intrahepatic HCV expression in transgenic mice without an interferon response. CONCLUSIONS: The present results indicate that the CL-LA5 we developed is a good vehicle to lead siRNA to the liver. Hence, CL-LA5 will be helpful for siRNA therapy targeting liver diseases, especially hepatitis C.
BACKGROUND/AIMS: RNA interference has considerable therapeutic potential, particularly for anti-viral therapy. We previously reported that hepatitis C virus (HCV)-directed small interfering RNA (siRNA; siE) efficiently inhibits HCV replication, using HCV replicon cells. To employ the siRNA as a therapeutic strategy, we attempted in vivo silencing of intrahepatic HCV gene expression by siE using a novel cationic liposome. METHODS: The liposomes consisted of conjugated lactose residues, based on the speculation that lactose residues would effectively deliver siRNA to the liver via a liver specific receptor. The lactosylated cationic liposome 5 (CL-LA5) that contained the most lactose residues introduced the most siRNA into a humanhepatoma cell line, which then inhibited replication of HCV replicons. RESULTS: In mice, the siRNA/CL-LA5 complexes accumulated primarily in the liver and were widespread throughout the hepatic parenchymal cells. Moreover, siE/CL-LA5 specifically and dose-dependently suppressed intrahepatic HCV expression in transgenic mice without an interferon response. CONCLUSIONS: The present results indicate that the CL-LA5 we developed is a good vehicle to lead siRNA to the liver. Hence, CL-LA5 will be helpful for siRNA therapy targeting liver diseases, especially hepatitis C.