Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain

AAV vectors that efficiently transduce the mouse brain after intravenous injection are generated with a CRE-dependent selection system. Recombinant adeno-associated viruses (rAAVs) are commonly used vehicles for in vivo gene transfer 1 , 2 , 3 , 4 , 5 , 6 . However, the tropism repertoire of natural...

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Bibliographic Details
Published in:Nature biotechnology 2016-02, Vol.34 (2), p.204-209
Main Authors: Deverman, Benjamin E, Pravdo, Piers L, Simpson, Bryan P, Kumar, Sripriya Ravindra, Chan, Ken Y, Banerjee, Abhik, Wu, Wei-Li, Yang, Bin, Huber, Nina, Pasca, Sergiu P, Gradinaru, Viviana
Format: Article
Language:English
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Adeno-associated virus
Agriculture
Animals
Bioinformatics
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Brain
Cellular biology
Central nervous system
Dependovirus - genetics
Female
Genes
Genetic aspects
Genetic Engineering - methods
Genetic transformation
Genetic variation
Genetic Vectors - genetics
HEK293 Cells
Humans
Integrases - genetics
Integrases - metabolism
letter
Life Sciences
Mice
Observations
Transfection - methods
Viruses
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Description
Summary:AAV vectors that efficiently transduce the mouse brain after intravenous injection are generated with a CRE-dependent selection system. Recombinant adeno-associated viruses (rAAVs) are commonly used vehicles for in vivo gene transfer 1 , 2 , 3 , 4 , 5 , 6 . However, the tropism repertoire of naturally occurring AAVs is limited, prompting a search for novel AAV capsids with desired characteristics 7 , 8 , 9 , 10 , 11 , 12 , 13 . Here we describe a capsid selection method, called Cre recombination–based AAV targeted evolution (CREATE), that enables the development of AAV capsids that more efficiently transduce defined Cre-expressing cell populations in vivo . We use CREATE to generate AAV variants that efficiently and widely transduce the adult mouse central nervous system (CNS) after intravenous injection. One variant, AAV-PHP.B, transfers genes throughout the CNS with an efficiency that is at least 40-fold greater than that of the current standard, AAV9 (refs. 14 , 15 , 16 , 17 ), and transduces the majority of astrocytes and neurons across multiple CNS regions. In vitro , it transduces human neurons and astrocytes more efficiently than does AAV9, demonstrating the potential of CREATE to produce customized AAV vectors for biomedical applications.
ISSN:1087-0156
1546-1696
DOI:10.1038/nbt.3440