MedStar Authors catalog › Details for: Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.
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Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.

by Sheikh, Farooq.
Citation: PLoS ONE [Electronic Resource]. 10(4):e0124411, 2015..Journal: PloS one.ISSN: 1932-6203.Full author list: 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.UI/PMID: 25923107.Subject(s): Animals | Carbon Tetrachloride | Cell Line | *Dependovirus/ge [Genetics] | Drug-Induced Liver Injury/ge [Genetics] | Drug-Induced Liver Injury/pa [Pathology] | *Drug-Induced Liver Injury/th [Therapy] | Extracellular Matrix/me [Metabolism] | Extracellular Matrix/pa [Pathology] | Gene Expression Regulation | *Genetic Vectors/ad [Administration & Dosage] | Genetic Vectors/me [Metabolism] | Hepatic Stellate Cells/me [Metabolism] | Hepatic Stellate Cells/pa [Pathology] | *Hepatocytes/me [Metabolism] | Hepatocytes/pa [Pathology] | Humans | Liver Cirrhosis/ci [Chemically Induced] | Liver Cirrhosis/ge [Genetics] | Liver Cirrhosis/pa [Pathology] | *Liver Cirrhosis/th [Therapy] | Mice | *MicroRNAs/ge [Genetics] | MicroRNAs/me [Metabolism] | Transforming Growth Factor beta/ai [Antagonists & Inhibitors] | Transforming Growth Factor beta/pd [Pharmacology]Institution(s): MedStar Heart & Vascular InstituteActivity type: Journal Article.Medline article type(s): Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tOnline resources: Click here to access online Digital Object Identifier: http://dx.doi.org/10.1371/journal.pone.0124411 (Click here) Abbreviated citation: PLoS ONE. 10(4):e0124411, 2015.Local Holdings: Available online through MWHC library: 2006 - present.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 (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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