Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle

被引：205

作者：

Asokan, Aravind ^{[1
,2
]}

Conway, Julia C. ^{[1
]}

Phillips, Jana L. ^{[1
]}

Li, Chengwen ^{[1
]}

Hegge, Julia ^{[4
]}

Sinnott, Rebecca ^{[1
]}

Yadav, Swati ^{[1
]}

DiPrimio, Nina ^{[1
]}

Nam, Hyun-Joo ^{[3
]}

Agbandje-McKenna, Mavis ^{[3
]}

McPhee, Scott ^{[5
]}

Wolff, Jon ^{[4
]}

Samulski, R. Jude ^{[1
]}

机构：

[1] Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC 27515 USA

[2] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[3] Univ Florida, Macromol Struct Grp, Gainesville, FL USA

[4] Mirus Bio Corp, Madison, WI USA

[5] Asklepios Biopharmaceut Inc, Chapel Hill, NC USA

来源：

NATURE BIOTECHNOLOGY | 2010年 / 28卷 / 01期

关键词：

VIRAL VECTORS; AAV VECTORS; HEPARIN-BINDING; EXPRESSION; SEROTYPES; IDENTIFICATION; THERAPY; TROPISM; TISSUE; TYPE-2;

D O I：

10.1038/nbt.1599

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Reengineering the receptor footprints of adeno-associated virus (AAV) isolates may yield variants with improved properties for clinical applications. We generated a panel of synthetic AAV2 vectors by replacing a hexapeptide sequence in a previously identified heparan sulfate receptor footprint with corresponding residues from other AAV strains. This approach yielded several chimeric capsids displaying systemic tropism after intravenous administration in mice. Of particular interest, an AAV2/AAV8 chimera designated AAV2i8 displayed an altered antigenic profile, readily traversed the blood vasculature, and selectively transduced cardiac and whole-body skeletal muscle tissues with high efficiency. Unlike other AAV serotypes, which are preferentially sequestered in the liver, AAV2i8 showed markedly reduced hepatic tropism. These features of AAV2i8 suggest that it is well suited to translational studies in gene therapy of musculoskeletal disorders.

引用

页码：79 / U107

页数：5

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