Systemic delivery of scAAV8-encoded MiR-29a ameliorates hepatic fibrosis in carbon tetrachloride-treated mice

Matthew K. Knabel, Kalyani Ramachandran, Sunil Karhadkar, Hun Way Hwang, Tyler J. Creamer, Raghu R. Chivukula, Farooq Sheikh, K. Reed Clark, Michael Torbenson, Robert A. Montgomery, Andrew M. Cameron, Joshua T. Mendell, Daniel S. Warren

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl<inf>4</inf>) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl<inf>4</inf>. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.

Original languageEnglish (US)
Article numbere0124411
JournalPLoS One
Volume10
Issue number4
DOIs
StatePublished - Apr 29 2015

Fingerprint

Dependovirus
carbon tetrachloride
liver cirrhosis
Carbon Tetrachloride
fibrosis
MicroRNAs
microRNA
Fibrosis
Viruses
extracellular matrix
Liver
Extracellular Matrix
mice
therapeutics
liver
hepatocytes
Hepatocytes
Down-Regulation
Genes
Hepatic Stellate Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Knabel, M. K., Ramachandran, K., Karhadkar, S., Hwang, H. W., Creamer, T. J., Chivukula, R. R., ... Warren, D. S. (2015). Systemic delivery of scAAV8-encoded MiR-29a ameliorates hepatic fibrosis in carbon tetrachloride-treated mice. PLoS One, 10(4), [e0124411]. https://doi.org/10.1371/journal.pone.0124411

Systemic delivery of scAAV8-encoded MiR-29a ameliorates hepatic fibrosis in carbon tetrachloride-treated mice. / Knabel, Matthew K.; Ramachandran, Kalyani; Karhadkar, Sunil; Hwang, Hun Way; Creamer, Tyler J.; Chivukula, Raghu R.; Sheikh, Farooq; Clark, K. Reed; Torbenson, Michael; Montgomery, Robert A.; Cameron, Andrew M.; Mendell, Joshua T.; Warren, Daniel S.

In: PLoS One, Vol. 10, No. 4, e0124411, 29.04.2015.

Research output: Contribution to journalArticle

Knabel, MK, Ramachandran, K, Karhadkar, S, Hwang, HW, Creamer, TJ, Chivukula, RR, Sheikh, F, Clark, KR, Torbenson, M, Montgomery, RA, Cameron, AM, Mendell, JT & Warren, DS 2015, 'Systemic delivery of scAAV8-encoded MiR-29a ameliorates hepatic fibrosis in carbon tetrachloride-treated mice', PLoS One, vol. 10, no. 4, e0124411. https://doi.org/10.1371/journal.pone.0124411
Knabel MK, Ramachandran K, Karhadkar S, Hwang HW, Creamer TJ, Chivukula RR et al. Systemic delivery of scAAV8-encoded MiR-29a ameliorates hepatic fibrosis in carbon tetrachloride-treated mice. PLoS One. 2015 Apr 29;10(4). e0124411. https://doi.org/10.1371/journal.pone.0124411
Knabel, Matthew K. ; Ramachandran, Kalyani ; Karhadkar, Sunil ; Hwang, Hun Way ; Creamer, Tyler J. ; Chivukula, Raghu R. ; Sheikh, Farooq ; Clark, K. Reed ; Torbenson, Michael ; Montgomery, Robert A. ; Cameron, Andrew M. ; Mendell, Joshua T. ; Warren, Daniel S. / Systemic delivery of scAAV8-encoded MiR-29a ameliorates hepatic fibrosis in carbon tetrachloride-treated mice. In: PLoS One. 2015 ; Vol. 10, No. 4.
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