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Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.
- Source :
-
PloS one [PLoS One] 2015 Apr 29; Vol. 10 (4), pp. e0124411. Date of Electronic Publication: 2015 Apr 29 (Print Publication: 2015). - Publication Year :
- 2015
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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-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 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.
- Subjects :
- Animals
Carbon Tetrachloride
Cell Line
Chemical and Drug Induced Liver Injury genetics
Chemical and Drug Induced Liver Injury pathology
Extracellular Matrix metabolism
Extracellular Matrix pathology
Gene Expression Regulation
Genetic Vectors metabolism
Hepatic Stellate Cells metabolism
Hepatic Stellate Cells pathology
Hepatocytes pathology
Humans
Liver Cirrhosis chemically induced
Liver Cirrhosis genetics
Liver Cirrhosis pathology
Mice
MicroRNAs metabolism
Transforming Growth Factor beta antagonists & inhibitors
Transforming Growth Factor beta pharmacology
Chemical and Drug Induced Liver Injury therapy
Dependovirus genetics
Genetic Vectors administration & dosage
Hepatocytes metabolism
Liver Cirrhosis therapy
MicroRNAs genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25923107
- Full Text :
- https://doi.org/10.1371/journal.pone.0124411