Article | Published:

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

Nature Biotechnology volume 26, pages 431442 (2008) | Download Citation

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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Acknowledgements

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

Author information

Author notes

    • Yasushi Sato
    • , Kazuyuki Murase
    •  & Junji Kato

    These authors contributed equally to this work.

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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Contributions

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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The authors declare no competing financial interests.

Corresponding author

Correspondence to Yoshiro Niitsu.

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DOI

https://doi.org/10.1038/nbt1396

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