MicroRNA-regulated, systemically delivered rAAV9: a step closer to CNS-restricted transgene expression
Ameres, Stefan L.
Ahmed, Seemin Seher
Mello, Craig C.
Flotte, Terence R.
Zamore, Phillip D.
UMass Chan AffiliationsProgram in Bioinformatics and Integrative Biology
Department of Pediatrics
Program in Molecular Medicine
Department of Biochemistry and Molecular Pharmacology
Department of Molecular Genetics and Microbiology
Gene Therapy Center
KeywordsCentral Nervous System
Genetics and Genomics
Medicine and Health Sciences
Nervous System Diseases
MetadataShow full item record
AbstractRecombinant 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.
SourceMol Ther. 2011 Mar;19(3):526-35. Epub 2010 Dec 21. Link to article on publisher's website
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/39448
Co-author Seemin Seher Ahmed is a doctoral student in the Interdisciplinary Graduate Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.
Related ResourcesLink to article in PubMed
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/