Gene Therapy Center; Department of Molecular Genetics and Microbiology; Department of Biochemistry and Molecular Pharmacology; Program in Molecular Medicine; Department of Pediatrics; Program in Bioinformatics
Central Nervous System; Dependovirus; Genetic Vectors; MicroRNAs; Transgenes
Genetics and Genomics | Life Sciences | Medicine and Health Sciences | Nervous System Diseases
Recombinant adeno-associated viruses (rAAVs) that can cross the blood-brain-barrier and achieve efficient and stable transvascular gene transfer to the central nervous system (CNS) hold significant promise for treating CNS disorders. However, following intravascular delivery, these vectors also target liver, heart, skeletal muscle, and other tissues, which may cause untoward effects. To circumvent this, we used tissue-specific, endogenous microRNAs (miRNAs) to repress rAAV expression outside the CNS, by engineering perfectly complementary miRNA-binding sites into the rAAV9 genome. This approach allowed simultaneous multi-tissue regulation and CNS-directed stable transgene expression without detectably perturbing the endogenous miRNA pathway. Regulation of rAAV expression by miRNA was primarily via site-specific cleavage of the transgene mRNA, generating specific 5' and 3' mRNA fragments. Our findings promise to facilitate the development of miRNA-regulated rAAV for CNS-targeted gene delivery and other applications.
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Citation: Mol Ther. 2011 Mar;19(3):526-35. Epub 2010 Dec 21. Link to article on publisher's website