Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.
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.
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Matthew K
MK
Knabel
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Kalyani
K
Ramachandran
Department of Surgery, Temple University School of Medicine, Philadelphia, PA, United States of America.
Sunil
S
Karhadkar
Laboratory of Molecular Neuro-oncology, Rockefeller University, New York, New York, United States of America.
Hun-Way
HW
Hwang
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Tyler J
TJ
Creamer
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Raghu R
RR
Chivukula
Department of Cardiology, Washington Hospital Center, Washington, DC, United States of America.
Farooq
F
Sheikh
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
K Reed
KR
Clark
Department of Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
Michael
M
Torbenson
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Robert A
RA
Montgomery
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Andrew M
AM
Cameron
Department of Molecular Biology, UT Southwestern Medical Center, Dallas, Texas, United States of America; Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, Texas, United States of America; Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, United States of America.
Joshua T
JT
Mendell
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Daniel S
DS
Warren
D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology
C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride