Overcoming Preexisting Humoral Immunity to AAV Using Capsid Decoys

被引：269

作者：

Mingozzi, Federico ^{[1
,2
]}

Anguela, Xavier M. ^{[1
,2
,3
]}

Pavani, Giulia ^{[1
,2
]}

Chen, Yifeng ^{[1
,2
,3
]}

Davidson, Robert J. ^{[1
,2
]}

Hui, Daniel J. ^{[1
,2
]}

Yazicioglu, Mustafa ^{[1
,2
]}

Elkouby, Liron ^{[1
,2
,3
]}

Hinderer, Christian J. ^{[1
,2
,4
]}

Faella, Armida ^{[1
,2
]}

Howard, Carolann ^{[1
,2
]}

Tai, Alex ^{[1
,2
]}

Podsakoff, Gregory M. ^{[1
,2
]}

Zhou, Shangzhen ^{[1
,2
]}

Basner-Tschakarjan, Etiena ^{[1
,2
]}

Wright, John Fraser ^{[1
,2
,5
]}

High, Katherine A. ^{[1
,2
,3
,5
]}

机构：

[1] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA

[3] Howard Hughes Med Inst, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Gene Therapy & Vaccine Program, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Dept Pediat Pathol & Lab Med, Philadelphia, PA 19104 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2013年 / 5卷 / 194期

关键词：

ADENOASSOCIATED VIRAL VECTORS; HUMAN GENE-THERAPY; NONHUMAN PRIMATE MODEL; HEMOPHILIA-B; FACTOR-IX; IN-VIVO; EFFICIENT TRANSDUCTION; SKELETAL-MUSCLE; HUMAN FIX; VIRUS;

D O I：

10.1126/scitranslmed.3005795

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Adeno-associated virus (AAV) vectors delivered through the systemic circulation successfully transduce various target tissues in animal models. However, similar attempts in humans have been hampered by the high prevalence of neutralizing antibodies to AAV, which completely block vector transduction. We show in both mouse and nonhuman primate models that addition of empty capsid to the final vector formulation can, in a dose-dependent manner, adsorb these antibodies, even at high titers, thus overcoming their inhibitory effect. To further enhance the safety of the approach, we mutated the receptor binding site of AAV2 to generate an empty capsid mutant that can adsorb antibodies but cannot enter a target cell. Our work suggests that optimizing the ratio of full/empty capsids in the final formulation of vector, based on a patient's anti-AAV titers, will maximize the efficacy of gene transfer after systemic vector delivery.

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页数：9

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