Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates.
Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates.
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抗体中和构成玻璃体内腺相关病毒载体基因递送至非人类灵长类动物的障碍。
DOI：
10.1038/gt.2014.115
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发表时间：
2015-02
期刊：
影响因子：
5.1
通讯作者：
Schaffer, D. V.
中科院分区：
文献类型：
--
作者：
Kotterman, M. A.;Yin, L.;Strazzeri, J. M.;Flannery, J. G.;Merigan, W. H.;Schaffer, D. V.
基于腺相关病毒（AAV）的基因传递载体在临床前疾病模型和针对多种疾病靶标的人体临床试验中都展现出了前景，包括视网膜退行性疾病、莱伯氏先天性黑蒙和无脉络膜血症。 AAV 面临的一项普遍挑战是，预先存在的免疫力以及载体施用后随后产生的免疫力会严重抑制全身 AAV 载体基因传递。然而，在大型动物中，中和抗体 (NAB) 在 AAV 转导被认为具有免疫特权的组织（例如眼睛）中的作用尚不清楚。玻璃体内 AAV 给药允许广泛的视网膜递送，但比视网膜下给药更容易与免疫系统相互作用。为了评估全身抗 AAV 抗体水平对玻璃体内基因传递的影响，我们对玻璃体内注射各种 AAV 衣壳之前和之后非人灵长类动物血清中存在的抗 AAV 抗体进行了定量。分析表明，无论衣壳血清型、转基因或注射病毒剂量如何，玻璃体内给药都会导致抗 AAV 抗体增加。对于注射野生型AAV2和/或AAV2突变体的猴子来说，最显着影响抗AAV2抗体产生的变量是递送的病毒量。此外，注射后抗体滴度针对所施用的血清型最高，但抗体也与其他 AAV 血清型发生交叉反应。此外，血清中的中和抗体水平与玻璃体液中的中和抗体水平相关，证明这种给药途径将 AAV 衣壳表位暴露于适应性免疫系统，并且血清测量可预测玻璃体液 NAB 滴度。此外，猴子血清中预先存在的中和抗体滴度的存在与玻璃体内注射 AAV 后转基因表达减弱、衰退或无转基因表达密切相关 (R=0.76)。研究抗 AAV 抗体的开发将有助于了解眼部给药期间基因治疗载体与免疫系统之间的相互作用，并可为未来应用玻璃体内基因递送的临床研究奠定基础。
Gene delivery vectors based on adeno-associated viruses (AAV) have exhibited promise in both preclinical disease models and human clinical trials for numerous disease targets, including the retinal degenerative disorders Leber's congenital amaurosis and choroideremia. One general challenge for AAV is that pre-existing immunity, as well as subsequent development of immunity following vector administration, can severely inhibit systemic AAV vector gene delivery. However, the role of neutralizing antibodies (NABs) in AAV transduction of tissues considered to be immune privileged, such as the eye, is unclear in large animals. Intravitreal AAV administration allows for broad retinal delivery, but is more susceptible to interactions with the immune system than subretinal administration. To assess the effects of systemic anti-AAV antibody levels on intravitreal gene delivery, we quantified the anti-AAV antibodies present in sera from non-human primates before and after intravitreal injections with various AAV capsids. Analysis showed that intravitreal administration resulted in an increase in anti-AAV antibodies regardless of the capsid serotype, transgene, or dosage of virus injected. For monkeys injected with wild-type AAV2 and/or an AAV2 mutant, the variable that most significantly affected the production of anti-AAV2 antibodies was the amount of virus delivered. In addition, post-injection antibody titers were highest against the serotype administered, but the antibodies were also cross-reactive against other AAV serotypes. Furthermore, neutralizing antibody levels in serum correlated with those in vitreal fluid, demonstrating both that this route of administration exposes AAV capsid epitopes to the adaptive immune system and that serum measurements are predictive of vitreous fluid NAB titers. Moreover, the presence of pre-existing neutralizing antibody titers in the serum of monkeys correlated strongly (R=0.76) with weak, decaying, or no transgene expression following intravitreal administration of AAV. Investigating anti-AAV antibody development will aid in understanding the interactions between gene therapy vectors and the immune system during ocular administration and can form a basis for future clinical studies applying intravitreal gene delivery.
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影响因子：
4.2
作者：
Cideciyan, Artur V.;Hauswirth, William W.;Jacobson, Samuel G.
通讯作者：
Jacobson, Samuel G.
影响因子：
--
作者：
Jacobson, Samuel G.;Cideciyan, Artur V.;Ratnakaram, Ramakrishna;Heon, Elise;Schwartz, Sharon B.;Roman, Alejandro J.;Peden, Marc C.;Aleman, Tomas S.;Boye, Sanford L.;Sumaroka, Alexander;Conlon, Thomas J.;Calcedo, Roberto;Pang, Ji-Jing;Erger, Kirsten E.;Olivares, Melani B.;Mullins, Cristina L.;Swider, Malgorzata;Kaushal, Shalesh;Feuer, William J.;Iannaccone, Alessandro;Fishman, Gerald A.;Stone, Edwin M.;Byrne, Barry J.;Hauswirth, William W.
通讯作者：
Hauswirth, William W.
影响因子：
4.4
作者：
Jacobson, Samuel G.;Aleman, Tomas S.;Kimberling, William J.
通讯作者：
Kimberling, William J.
影响因子：
5.4
作者：
Halbert, CL;Standaert, TA;Miller, AD
通讯作者：
Miller, AD
影响因子：
4.2
作者：
Hauswirth, William W.;Aleman, Tomas S.;Jacobson, Samuel G.
通讯作者：
Jacobson, Samuel G.