Effects of Fibrotic Tissue on Liver-targeted Hydrodynamic Gene Delivery

Yuji Kobayashi; Kenya Kamimura; Hiroyuki Abe; Takeshi Yokoo; Kohei Ogawa; Yoko Shinagawa-Kobayashi; Ryo Goto; Ryosuke Inoue; Masato Ohtsuka; Hiromi Miura; Tsutomu Kanefuji; Takeshi Suda; Masanori Tsuchida; Yutaka Aoyagi; Guisheng Zhang; Dexi Liu; Shuji Terai

doi:10.1038/mtna.2016.63

Molecular Therapy: Nucleic Acids (Jan 2016)

Effects of Fibrotic Tissue on Liver-targeted Hydrodynamic Gene Delivery

Yuji Kobayashi,
Kenya Kamimura,
Hiroyuki Abe,
Takeshi Yokoo,
Kohei Ogawa,
Yoko Shinagawa-Kobayashi,
Ryo Goto,
Ryosuke Inoue,
Masato Ohtsuka,
Hiromi Miura,
Tsutomu Kanefuji,
Takeshi Suda,
Masanori Tsuchida,
Yutaka Aoyagi,
Guisheng Zhang,
Dexi Liu,
Shuji Terai

Affiliations

Yuji Kobayashi: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Kenya Kamimura: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Hiroyuki Abe: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Takeshi Yokoo: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Kohei Ogawa: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Yoko Shinagawa-Kobayashi: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Ryo Goto: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Ryosuke Inoue: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Masato Ohtsuka: Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, Isehara, Kanagawa, Japan
Hiromi Miura: Department of Regenerative Medicine, Basic Medical Science, School of Medicine, Tokai University, Isehara, Kanagawa, Japan
Tsutomu Kanefuji: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Takeshi Suda: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Masanori Tsuchida: Division of Thoracic and Cardiovascular Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Yutaka Aoyagi: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
Guisheng Zhang: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, USA
Dexi Liu: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, USA
Shuji Terai: Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan

DOI: https://doi.org/10.1038/mtna.2016.63
Journal volume & issue: Vol. 5, no. C

Abstract

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Hydrodynamic gene delivery is a common method for gene transfer to the liver of small animals, and its clinical applicability in large animals has been demonstrated. Previous studies focused on functional analyses of therapeutic genes in animals with normal livers and little, however, is known regarding its effectiveness and safety in animals with liver fibrosis. Therefore, this study aimed to examine the effects of liver fibrosis on hydrodynamic gene delivery efficiency using a rat liver fibrosis model. We demonstrated for the first time, using pCMV-Luc plasmid, that this procedure is safe and that the amount of fibrotic tissue in the liver decreases gene delivery efficiency, resulting in decrease in luciferase activity depending on the volume of fibrotic tissue in the liver and the number of hepatocytes that are immunohistochemically stained positive for transgene product. We further demonstrate that antifibrotic gene therapy with matrix metalloproteinase-13 gene reduces liver fibrosis and improves efficiency of hydrodynamic gene delivery. These results demonstrate the negative effects of fibrotic tissue on hydrodynamic gene delivery and its recovery by appropriate antifibrotic therapy.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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