Watanabe Tsunamasa, Umehara Takuya, Yasui Fumihiko, Nakagawa Shin-Ichiro, Yano Junichi, Ohgi Tadaaki, Sonoke Satoru, Satoh Kenichi, Inoue Kazuaki, Yoshiba Makoto, Kohara Michinori
Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
J Hepatol. 2007 Dec;47(6):744-50. doi: 10.1016/j.jhep.2007.06.015. Epub 2007 Jul 26.
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.
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.
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.
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.
背景/目的：RNA干扰具有巨大的治疗潜力，尤其是在抗病毒治疗方面。我们之前报道过，针对丙型肝炎病毒（HCV）的小干扰RNA（siRNA；siE）利用HCV复制子细胞能有效抑制HCV复制。为了将该siRNA用作一种治疗策略，我们尝试使用一种新型阳离子脂质体，通过siE在体内沉默肝内HCV基因表达。
基于乳糖残基可通过肝脏特异性受体将siRNA有效递送至肝脏的推测，这些脂质体由共轭乳糖残基组成。含有最多乳糖残基的乳糖基化阳离子脂质体5（CL-LA5）将最多的siRNA导入人肝癌细胞系，进而抑制HCV复制子的复制。
在小鼠中，siRNA/CL-LA5复合物主要在肝脏中蓄积，并广泛分布于肝实质细胞中。此外，siE/CL-LA5在无干扰素应答的转基因小鼠中特异性且剂量依赖性地抑制肝内HCV表达。
目前的结果表明，我们研发的CL-LA5是一种能将siRNA导向肝脏的良好载体。因此，CL-LA5将有助于针对肝脏疾病尤其是丙型肝炎的siRNA治疗。
