Current Gene Therapy

Ignacio Anegon
Director INSERM UMR 1064-Center for Research in Transplantation and Immunology
CHU de Nantes. 30, boulevard
Nantes
France

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Foxf1 siRNA Delivery to Hepatic Stellate Cells by DBTC Lipoplex Formulations Ameliorates Fibrosis in Livers of Bile Duct Ligated Mice

Author(s): Kerstin Abshagen, Malte Brensel, Berit Genz, Kira Roth, Maria Thomas, Volker Fehring, Ute Schaeper, Brigitte Vollmar.

Abstract:

Activation of hepatic stellate cells (HSCs) is a key event in pathogenesis of liver fibrosis and represents an orchestral interplay of inhibiting and activating transcription factors like forkhead box f1 (Foxf1), being described to stimulate pro-fibrogenic genes in HSCs. Here, we evaluated a lipidbased liver-specific delivery system (DBTC) suitable to transfer Foxf1 siRNA specifically to HSCs and examined its antifibrotic potential on primary HSCs and LX-2 cells as well as in a murine model of bile duct ligation (BDL)-induced secondary cholestasis. Foxf1 silencing reduced proliferation capacity and attenuated contractility of HSCs. Systemic administration of DBTC-lipoplexes in mice was sufficient to specifically silence genes expressed in different liver cell types. Using intravital and immunofluorescence microscopy we confirmed the specific delivery of Cy3-labeled DBTC to the liver, and particularly to HSCs. Repeated treatment with DBTC-lipoplexes resulted in siRNA-mediated silencing of Foxf1 early after BDL and finally attenuated progression of the fibrotic process. Decreased HSC activation in-effect ameliorated liver injury as shown by substantial reduction of necrotic area and deposition of extracellular matrix. Our findings suggest that Foxf1 may serve as a target gene to disrupt progression of liver fibrosis and DBTC might provide a potentially feasible and effective tool for HSC-specific delivery of therapeutic RNA.

Keywords: Cholestasis, chronic liver disease, intravital microscopy, lipoplex, mouse, silencing.

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Article Details

VOLUME: 15
ISSUE: 3
Year: 2015
Page: [215 - 227]
Pages: 13
DOI: 10.2174/1566523215666150126114634
Price: $58