Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.

MedStar author(s):
Citation: PLoS ONE [Electronic Resource]. 10(4):e0124411, 2015.PMID: 25923107Institution: MedStar Heart & Vascular InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Dependovirus/ge [Genetics] | *Drug-Induced Liver Injury/th [Therapy] | *Genetic Vectors/ad [Administration & Dosage] | *Hepatocytes/me [Metabolism] | *Liver Cirrhosis/th [Therapy] | *MicroRNAs/ge [Genetics] | Animals | Carbon Tetrachloride | Cell Line | Drug-Induced Liver Injury/ge [Genetics] | Drug-Induced Liver Injury/pa [Pathology] | Extracellular Matrix/me [Metabolism] | Extracellular Matrix/pa [Pathology] | Gene Expression Regulation | Genetic Vectors/me [Metabolism] | Hepatic Stellate Cells/me [Metabolism] | Hepatic Stellate Cells/pa [Pathology] | Hepatocytes/pa [Pathology] | Humans | Liver Cirrhosis/ci [Chemically Induced] | Liver Cirrhosis/ge [Genetics] | Liver Cirrhosis/pa [Pathology] | Mice | MicroRNAs/me [Metabolism] | Transforming Growth Factor beta/ai [Antagonists & Inhibitors] | Transforming Growth Factor beta/pd [Pharmacology]Year: 2015Local holdings: Available online through MWHC library: 2006 - presentISSN:
  • 1932-6203
Name of journal: PloS oneAbstract: 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 (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-beta. 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 CCl4. 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.All authors: Cameron AM, Chivukula RR, Clark KR, Creamer TJ, Hwang HW, Karhadkar S, Knabel MK, Mendell JT, Montgomery RA, Ramachandran K, Sheikh F, Torbenson M, Warren DSFiscal year: FY2016Digital Object Identifier: Date added to catalog: 2016-05-24
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 25923107 Available 25923107

Available online through MWHC library: 2006 - present

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 (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-beta. 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 CCl4. 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.

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