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Using Cre-Dependent In Vivo Selection to Identify AAV Variants That Enable Efficient and Widespread Gene Transfer to the Adult Central Nervous System

Deverman, Benjamin E. and Pravdo, Piers L. and Simpson, Bryan P. and Ravindra Kumar, Sripriya and Luo, Yicheng and Chan, Ken Y. and Banerjee, Abhik and Wu, Wei-Li and Yang, Bin and Huber, Nina and Pasca, Sergiu P. and Gradinaru, Viviana (2016) Using Cre-Dependent In Vivo Selection to Identify AAV Variants That Enable Efficient and Widespread Gene Transfer to the Adult Central Nervous System. Molecular Therapy, 24 (S1). S99. ISSN 1525-0016.

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Recombinant adeno-associated viruses (rAAVs) are commonly used vehicles for in vivo gene transfer. However, the tropism repertoire of naturally occurring AAVs is limited, prompting the development of novel AAV capsids with more desirable transduction characteristics. We have developed a capsid selection method, called Cre-recombination-based AAV targeted evolution (CREATE), that enables the identification of AAV capsids that more efficiently transduce defined cell populations in vivo (Deverman et al. in press, Nature Biotechnology). We generated AAV capsid libraries and used CREATE to identify variants that cross the blood brain barrier and efficiently and widely transduce astrocytes in the mouse central nervous system (CNS) after intravenous injection. One variant, AAVPHP. B, transfers genes throughout the adult CNS with an efficiency that is 40- to 92-fold greater (depending on the CNS region) than that of the current standard, AAV9. It transduces the majority of astrocytes and neurons across multiple CNS regions, and in vitro, it transduces human neurons and astrocytes more efficiently than does AAV9. We are now evolving AAV-PHP.B for even greater transduction of specific CNS cell types as a means to both develop more effective vectors and to gain insight into the mechanism of enhanced transduction. Our identification of AAV-PHP.B and several other enhanced vectors after only two rounds of selection establishes CREATE as a powerful method to customize AAV vectors for biomedical applications.

Item Type:Article
Related URLs:
URLURL TypeDescription
Deverman, Benjamin E.0000-0002-6223-9303
Ravindra Kumar, Sripriya0000-0001-6033-7631
Luo, Yicheng0000-0003-3704-2389
Chan, Ken Y.0000-0002-8853-5186
Wu, Wei-Li0000-0003-2610-1881
Gradinaru, Viviana0000-0001-5868-348X
Additional Information:© 2016 The American Society of Gene & Cell Therapy.
Issue or Number:S1
Record Number:CaltechAUTHORS:20160527-092723542
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67433
Deposited By: Tony Diaz
Deposited On:27 May 2016 16:37
Last Modified:09 Mar 2020 13:19

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