Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia
Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia
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DOI：
10.1038/gt.2011.90
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发表时间：
2012-03-01
期刊：
影响因子：
5.1
通讯作者：
Monahan, P. E.
中科院分区：
文献类型：
--
作者：
Li, C.;Narkbunnam, N.;Monahan, P. E.
重组腺相关病毒(RAAV)是一种很有前途的基因传递载体，近年来已被用于血友病患者的治疗。AAV应用的局限性之一是大多数人经历过野生型AAV 2型暴露，这种暴露经常产生中和抗体(NAB)，可能抑制rAAV2载体转导。使用其他血清型的rAAV载体可能会绕过这个问题。我们通过检测参加多机构血友病临床试验(联合结果研究)的62名血友病A儿童前瞻性收集的血清，调查了儿童早期NAB的发展。AAV2、AAV5和AAV8型在血友病治疗中的临床应用已被建议，因此针对这些血清型的NAB在中位数4年的随访中被连续检测。在儿童早期，所有血清型的NABS患病率都有所增加。与AAV5(25.8%)和AAV8(22.6%)相比，对AAV2(43.5%)的NAB出现频率更高，滴度也更高。在没有AAV2共同流行且效价较高的NAB的情况下，很少观察到针对AAV5或AAV8的NAB，这表明在AAV2暴露后，由于AAV2导向的NAB的部分交叉反应，检测到了针对AAV5和AAV8的NAB。这一结果可能指导使用替代AAV血清型的临床试验的合理设计，并表明接受AAV基因治疗的年轻患者将受益于较低的NABS患病率。基因治疗(2012年)19,288-294；DOI：10.1038/gt.2011.90；2011年6月23日在线发布
Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs. Gene Therapy (2012) 19, 288-294; doi:10.1038/gt.2011.90; published online 23 June 2011