252. Using Cre-Dependent In Vivo Selection to Identify AAV Variants That Enable Efficient and Widespread Gene Transfer to the Adult Central Nervous System
2016
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.
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