000			04196nam a22006137a 4500
008			160219s20152015 xxu||||| |||| 00| 0 eng d
022			_a1932-6203
040			_aOvid MEDLINE(R)
099			_a25923107
245			_aSystemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.
251			_aPLoS ONE [Electronic Resource]. 10(4):e0124411, 2015.
252			_aPLoS ONE. 10(4):e0124411, 2015.
253			_aPloS one
260			_c2015
260			_fFY2016
266			_d2016-05-24
501			_aAvailable online through MWHC library: 2006 - present
520			_aFibrosis 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.
546			_aEnglish
650			_a*Dependovirus/ge [Genetics]
650			_a*Drug-Induced Liver Injury/th [Therapy]
650			_a*Genetic Vectors/ad [Administration & Dosage]
650			_a*Hepatocytes/me [Metabolism]
650			_a*Liver Cirrhosis/th [Therapy]
650			_a*MicroRNAs/ge [Genetics]
650			_aAnimals
650			_aCarbon Tetrachloride
650			_aCell Line
650			_aDrug-Induced Liver Injury/ge [Genetics]
650			_aDrug-Induced Liver Injury/pa [Pathology]
650			_aExtracellular Matrix/me [Metabolism]
650			_aExtracellular Matrix/pa [Pathology]
650			_aGene Expression Regulation
650			_aGenetic Vectors/me [Metabolism]
650			_aHepatic Stellate Cells/me [Metabolism]
650			_aHepatic Stellate Cells/pa [Pathology]
650			_aHepatocytes/pa [Pathology]
650			_aHumans
650			_aLiver Cirrhosis/ci [Chemically Induced]
650			_aLiver Cirrhosis/ge [Genetics]
650			_aLiver Cirrhosis/pa [Pathology]
650			_aMice
650			_aMicroRNAs/me [Metabolism]
650			_aTransforming Growth Factor beta/ai [Antagonists & Inhibitors]
650			_aTransforming Growth Factor beta/pd [Pharmacology]
651			_aMedStar Heart & Vascular Institute
657			_aJournal Article
657			_aResearch Support, N.I.H., Extramural
657			_aResearch Support, Non-U.S. Gov't
700			_aSheikh, Farooq
790			_aCameron AM, Chivukula RR, Clark KR, Creamer TJ, Hwang HW, Karhadkar S, Knabel MK, Mendell JT, Montgomery RA, Ramachandran K, Sheikh F, Torbenson M, Warren DS
856			_uhttp://dx.doi.org/10.1371/journal.pone.0124411 _zhttp://dx.doi.org/10.1371/journal.pone.0124411
942			_cART _dArticle
999			_c1742 _d1742