title: Long-term, efficient inhibition of microRNA function in mice using rAAV vectors.
abstract: Understanding the function of individual microRNA (miRNA) species in mice would require the production of hundreds of loss-of-function strains. To accelerate analysis of miRNA biology in mammals, we combined recombinant adeno-associated virus (rAAV) vectors with miRNA 'tough decoys' (TuDs) to inhibit specific miRNAs. Intravenous injection of rAAV9 expressing anti-miR-122 or anti-let-7 TuDs depleted the corresponding miRNA and increased its mRNA targets. rAAV producing anti-miR-122 TuD but not anti-let-7 TuD reduced serum cholesterol by >30% for 25 weeks in wild-type mice. High-throughput sequencing of liver miRNAs from the treated mice confirmed that the targeted miRNAs were depleted and revealed that TuDs induced miRNA tailing and trimming in vivo. rAAV-mediated miRNA inhibition thus provides a simple way to study miRNA function in adult mammals and a potential therapy for dyslipidemia and other diseases caused by miRNA deregulation.
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Ameres
authors.forename: Randall
authors.initials: R
authors.lastname: Friedline
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Hung
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.forename: Ran
authors.initials: R
authors.lastname: He
authors.forename: Mengxin
authors.initials: M
authors.lastname: Li
authors.forename: Huapeng
authors.initials: H
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Mu
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Broderick
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Zamore
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics
chemical_list: D035683:MicroRNAs; D016372:RNA, Antisense; D011994:Recombinant Proteins; D002784:Cholesterol