Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina.
Vectors based on adeno-associated virus serotype 2 (AAV2) have been used extensively in many gene-delivery applications, including several successful clinical trials for one type of Leber congenital amaurosis in the retina. Many studies have focused on improving AAV2 transduction efficiency and cellular specificity by genetically engineering its capsid. We have previously shown that vectors-containing single-point mutations of capsid surface tyrosines in serotypes AAV2, AAV8, and AAV9 displayed significantly increased transduction efficiency in the retina compared with their wild-type counterparts. In the present study, we evaluated the transduction characteristics of AAV2 vectors containing combinations of multiple tyrosine to phenylalanine mutations in seven highly conserved surface-exposed capsid tyrosine residues following subretinal or intravitreal delivery in adult mice. The multiply mutated vectors exhibited different in vivo transduction properties, with some having a unique ability of transgene expression in all retinal layers. Such novel vectors may be useful in developing valuable new therapeutic strategies for the treatment of many genetic diseases.
Department of Ophthalmology, University of Florida, Gainesville, FL, USA.
Hilda
H
Petrs-Silva
Astra
A
Dinculescu
Qiuhong
Q
Li
Wen-Tao
WT
Deng
Ji-Jing
JJ
Pang
Seok-Hong
SH
Min
Vince
V
Chiodo
Andy W
AW
Neeley
Lakshmanan
L
Govindasamy
Antonette
A
Bennett
Mavis
M
Agbandje-McKenna
Li
L
Zhong
Baozheng
B
Li
Giridhara R
GR
Jayandharan
Arun
A
Srivastava
Alfred S
AS
Lewin
William W
WW
Hauswirth
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017354:Point Mutation / Q000235:genetics; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000235:genetics*
D014443:Tyrosine