Liver target delivery of small interfering RNA to the HCV gene by lactosylated cationic liposome.
OBJECTIVE
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.
Watanabe
Tsunamasa
T
Department of Microbiology and Cell Biology, The Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan.
Umehara
Takuya
T
Yasui
Fumihiko
F
Nakagawa
Shin-Ichiro
S
Yano
Junichi
J
Ohgi
Tadaaki
T
Sonoke
Satoru
S
Satoh
Kenichi
K
Inoue
Kazuaki
K
Yoshiba
Makoto
M
Kohara
Michinori
M
D000818:Animals; D002412:Cations; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D020868:Gene Silencing / Q000187:drug effects; D016679:Genome, Viral / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D007785:Lactose; D008081:Liposomes / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D016896:Treatment Outcome