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

Nature Biotechnology volume 26, pages 431–442 (2008)Cite this article

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 CCl4 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.

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Figure 1: Suppressive effect of siRNAgp46 on gp46 expression and collagen synthesis and RBP receptor dependent uptake of VA-lip-siRNAgp46-FAM by HS cells.
Figure 2: Specific delivery of VA-lip-siRNAgp46 to HS cells in cirrhotic rats.
Figure 3: Effect of i.v. injected VA-lip-siRNAgp46 on cirrhotic rat survival.
Figure 4: Effect of i.v. injection of VA-lip-siRNAgp46 on liver histology of cirrhotic rat.
Figure 5: Effect of i.v. injection of VA-lip-siRNAgp46 on CCl4-treated cirrhotic rats.
Figure 6: Effect of i.v. injection of VA-lip-siRNAgp46 on BDL-induced cirrhotic rats.

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Acknowledgements

This work was supported by grants-in-aid from Japan Society for the Promotion of Science to Y.S.

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  1. Yasushi Sato, Kazuyuki Murase and Junji Kato: These authors contributed equally to this work.

Authors and Affiliations

  1. Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, 060-8543, Japan

    Yasushi Sato, Kazuyuki Murase, Junji Kato, Masayoshi Kobune, Tsutomu Sato, Yutaka Kawano, Rishu Takimoto, Kouichi Takada, Koji Miyanishi, Takuya Matsunaga, Tetsuji Takayama & Yoshiro Niitsu

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Y.S., K. Murase and J.K. designed research, performed experiments and wrote the paper. M.K., T.S., Y.K., R.T., K.T., K. Miyanishi, T.M. and T.T. performed experiments. Y.N. designed research, wrote the paper and supervised the whole project. All authors discussed the results and commented on the manuscript.

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Correspondence to Yoshiro Niitsu.

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Sato, Y., Murase, K., Kato, J. et al. Resolution of liver cirrhosis using vitamin A–coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol 26, 431–442 (2008). https://doi.org/10.1038/nbt1396

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