Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo.
Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo.
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DOI：
10.1016/j.biomaterials.2014.05.032
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发表时间：
2014-08
期刊：
影响因子：
14
通讯作者：
Maguire, Casey A.
中科院分区：
文献类型：
--
作者：
Gyoergy, Bence;Fitzpatrick, Zachary;Crommentuijn, Matheus H. W.;Mu, Dakai;Maguire, Casey A.
腺相关病毒（adeno-associated virus，AAV）是西方世界第一个获得临床批准的基因治疗产品。为了开发AAV用于广泛的患者基础中的未来临床应用，特别是在需要静脉内（i. v.）在施用载体的情况下，病毒必须能够逃避针对野生型病毒的预先存在的抗体。在这里，我们证明了在小鼠中，与细胞外囊泡（EV）相关的AAV载体可以逃避人抗AAV中和抗体。我们观察到不同的抗体逃避和基因转移能力与不同的离心力分离的EV群体。EV相关的AAV载体（ev-AAV）在体外相对于标准AAV载体在一定范围的中和抗体浓度上的抗性高达136倍。重要的是，在小鼠中，在使静脉内施用的脑的标准AAV转导降低80%的被动转移的人抗体的浓度下，ev-AAV转导的转导没有降低并且高4，000倍。最后，我们表明，在EV表面上表达脑靶向肽允许与非靶向ev-AAV相比显著增强转导。使用ev-AAV代表了一种有效的、临床相关的方法，以在载体的全身施用后逃避人中和抗AAV抗体。
Recently adeno-associated virus (AAV) became the first clinically approved gene therapy product in the western world. To develop AAV for future clinical application in a widespread patient base, particularly in therapies which require intravenous (i.v.) administration of vector, the virus must be able to evade pre-existing antibodies to the wild type virus. Here we demonstrate that in mice, AAV vectors associated with extracellular vesicles (EVs) can evade human anti-AAV neutralizing antibodies. We observed different antibody evasion and gene transfer abilities with populations of EVs isolated by different centrifugal forces. EV-associated AAV vector (ev-AAV) was up to 136-fold more resistant over a range of neutralizing antibody concentrations relative to standard AAV vector in vitro. Importantly in mice, at a concentration of passively transferred human antibodies which decreased i.v. administered standard AAV transduction of brain by 80%, transduction of ev-AAV transduction was not reduced and was 4,000-fold higher. Finally, we show that expressing a brain targeting peptide on the EV surface allowed significant enhancement of transduction compared to untargeted ev-AAV. Using ev-AAV represents an effective, clinically relevant approach to evade human neutralizing anti-AAV antibodies after systemic administration of vector.
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DOI：
10.1038/mt.2008.1
发表时间：
2008-04
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Dai S;Wei D;Wu Z;Zhou X;Wei X;Huang H;Li G
通讯作者：
Li G
影响因子：
64.8
作者：
Feng Z;Hensley L;McKnight KL;Hu F;Madden V;Ping L;Jeong SH;Walker C;Lanford RE;Lemon SM
通讯作者：
Lemon SM
影响因子：
20.3
作者：
Jiang, Haiyan;Couto, Linda B.;Pierce, Glenn F.
通讯作者：
Pierce, Glenn F.
影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
12.4
作者：
Maguire, Casey A.;Balaj, Leonora;Skog, Johan
通讯作者：
Skog, Johan