Title

Long-term, efficient inhibition of microRNA function in mice using rAAV vectors

UMMS Affiliation

Gene Therapy Center; Department of Microbiology and Physiology Systems; Department of Biochemistry and Molecular Pharmacology; Mouse Phenotyping Center; Program in Molecular Medicine; Program in Bioinformatics and Integrative Biology; Department of Pediatrics

Date

3-4-2012

Document Type

Article

Medical Subject Headings

Dependovirus; Genetic Vectors; MicroRNAs; Dyslipidemias

Disciplines

Allergy and Immunology | Nutritional and Metabolic Diseases | Pediatrics | Respiratory Tract Diseases

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.

Comments

Citation: Nat Methods. 2012 Mar 4;9(4):403-9. doi: 10.1038/nmeth.1903. Link to article on publisher's site

Co-author Jennifer A. Broderick is a student in the Neuroscience program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to article in PubMed

Keywords

UMCCTS funding

PubMed ID

22388288