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A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A

Lookup NU author(s): Dr Mujdat Zeybel, Dr Saimir Luli, Laura Sabater, Dr Timothy Hardy, Professor Fiona Oakley, Dr Agata Page, Victoria Sharkey, Dr Daniela Di Paolo, Edgar Mendivil Rangel, Professor Jelena Mann, Professor Derek Mann

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

The progression of fibrosis in chronic liver disease is dependent upon hepatic stellate cells (HSCs) transdifferentiating to a myofibroblast-like phenotype. This pivotal process is controlled by enzymes that regulate histone methylation and chromatin structure, which may be targets for developing anti-fibrotics. There is limited pre-clinical experimental support for the potential to therapeutically manipulate epigenetic regulators in fibrosis. In order to learn if epigenetic treatment can halt the progression of pre-established liver fibrosis, we treated mice with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep) in a naked form or by selectively targeting HSC-derived myofibroblasts via an antibody-liposome-DZNep targeting vehicle. We discovered that DZNep treatment inhibited multiple histone methylation modifications, indicative of a broader specificity than previously reported. This broad epigenetic repression was associated with the suppression of fibrosis progression as assessed both histologically and biochemically. The anti-fibrotic effect of DZNep was reproduced when the drug was selectively targeted to HSC-derived myofibroblasts. Therefore, the in vivo modulation of HSC histone methylation is sufficient to halt progression of fibrosis in the context of continuous liver damage. This discovery and our novel HSC-targeting vehicle, which avoids the unwanted effects of epigenetic drugs on parenchymal liver cells, represents an important proof-of-concept for epigenetic treatment of liver fibrosis.


Publication metadata

Author(s): Zeybel M, Luli S, Sabater L, Hardy T, Oakley F, Leslie J, Page A, Salvador EM, Sharkey V, Tsukamoto H, Chu DCK, Singh US, Ponzoni M, Perri P, Di Paolo D, Mendivil EJ, Mann J, Mann DA

Publication type: Article

Publication status: Published

Journal: Molecular Therapy

Year: 2017

Volume: 25

Issue: 1

Pages: 218-231

Print publication date: 04/01/2017

Online publication date: 04/01/2017

Acceptance date: 21/10/2016

Date deposited: 24/02/2017

ISSN (print): 1525-0016

ISSN (electronic): 1525-0024

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.ymthe.2016.10.004

DOI: 10.1016/j.ymthe.2016.10.004


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