A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis

Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A

Müjdat Zeybel, Saimir Luli, Laura Sabater, Timothy Hardy, Fiona Oakley, Jack Leslie, Agata Page, Eva Moran Salvador, Victoria Sharkey, Hidekazu Tsukamoto, David C K Chu, Uma Sharan Singh, Mirco Ponzoni, Patrizia Perri, Daniela Di Paolo, Edgar J Mendivil, Jelena Mann, Derek A Mann

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)218-231
Number of pages14
JournalMolecular Therapy
Volume25
Issue number1
DOIs
Publication statusPublished - Jan 4 2017

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Hepatic Stellate Cells
Cell- and Tissue-Based Therapy
Epigenomics
Liver Cirrhosis
Fibrosis
Myofibroblasts
Methylation
Histones
Epigenetic Repression
Histone Code
Liver
Liposomes
Pharmaceutical Preparations
Chromatin
Liver Diseases
Chronic Disease
Therapeutics
3-deazaneplanocin
Phenotype
Antibodies

Keywords

  • Adenosine
  • Animals
  • Biomarkers
  • Carbon Tetrachloride
  • Collagen Type I
  • Disease Models, Animal
  • Disease Progression
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Hepatic Stellate Cells
  • Histone-Lysine N-Methyltransferase
  • Histones
  • Liver Cirrhosis
  • Male
  • Mice
  • Myofibroblasts
  • Journal Article

Cite this

A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis : Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A. / Zeybel, Müjdat; Luli, Saimir; Sabater, Laura; Hardy, Timothy; Oakley, Fiona; Leslie, Jack; Page, Agata; Moran Salvador, Eva; Sharkey, Victoria; Tsukamoto, Hidekazu; Chu, David C K; Singh, Uma Sharan; Ponzoni, Mirco; Perri, Patrizia; Di Paolo, Daniela; Mendivil, Edgar J; Mann, Jelena; Mann, Derek A.

In: Molecular Therapy, Vol. 25, No. 1, 04.01.2017, p. 218-231.

Research output: Contribution to journalArticle

Zeybel, M, Luli, S, Sabater, L, Hardy, T, Oakley, F, Leslie, J, Page, A, Moran Salvador, E, Sharkey, V, Tsukamoto, H, Chu, DCK, Singh, US, Ponzoni, M, Perri, P, Di Paolo, D, Mendivil, EJ, Mann, J & Mann, DA 2017, 'A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis: Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A', Molecular Therapy, vol. 25, no. 1, pp. 218-231. https://doi.org/10.1016/j.ymthe.2016.10.004
Zeybel, Müjdat ; Luli, Saimir ; Sabater, Laura ; Hardy, Timothy ; Oakley, Fiona ; Leslie, Jack ; Page, Agata ; Moran Salvador, Eva ; Sharkey, Victoria ; Tsukamoto, Hidekazu ; Chu, David C K ; Singh, Uma Sharan ; Ponzoni, Mirco ; Perri, Patrizia ; Di Paolo, Daniela ; Mendivil, Edgar J ; Mann, Jelena ; Mann, Derek A. / A Proof-of-Concept for Epigenetic Therapy of Tissue Fibrosis : Inhibition of Liver Fibrosis Progression by 3-Deazaneplanocin A. In: Molecular Therapy. 2017 ; Vol. 25, No. 1. pp. 218-231.
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AU - Sabater, Laura

AU - Hardy, Timothy

AU - Oakley, Fiona

AU - Leslie, Jack

AU - Page, Agata

AU - Moran Salvador, Eva

AU - Sharkey, Victoria

AU - Tsukamoto, Hidekazu

AU - Chu, David C K

AU - Singh, Uma Sharan

AU - Ponzoni, Mirco

AU - Perri, Patrizia

AU - Di Paolo, Daniela

AU - Mendivil, Edgar J

AU - Mann, Jelena

AU - Mann, Derek A

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N2 - 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.

AB - 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.

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KW - Epigenesis, Genetic

KW - Gene Expression Profiling

KW - Gene Expression Regulation

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KW - Histone-Lysine N-Methyltransferase

KW - Histones

KW - Liver Cirrhosis

KW - Male

KW - Mice

KW - Myofibroblasts

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DO - 10.1016/j.ymthe.2016.10.004

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EP - 231

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

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ER -