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Advances and challenges in human AAV-mediated gene transfer: Immunological insights from a mouse model of human glycosylation.

机译：人类AAV介导的基因转移的进展和挑战：人类糖基化小鼠模型的免疫学见解。

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摘要

Successful gene transfer for monogenic human disease can potentially provide a singularly administered, lifelong cure. Yet concerns remain over the safety and efficacy of gene transfer. Adeno-associated virus (AAV) is a commonly used gene transfer vector that is predominantly non-integrating, can transduce and persist in non-dividing cells, and is relatively non-inflammatory. AAV's have seen extensive pre-clinical success in animal models of Hemophilia B, with recent efficacy in the clinic. In both muscle-directed and liver-directed gene transfer of Factor IX (F.IX), multi-year expression of F.IX from AAV was observed in mice, dogs, and non-human primates. However, muscle-directed transfer to Hemophilia B human subjects resulted in sub therapeutic circulating F.IX, and liver-directed transfer led to transient therapeutic F.IX plasma levels that were eliminated by a hepatocyte-clearing CD8 T cell response directed against the AAV capsid. Thus the challenge of maintaining long-term, clinically meaningful levels of F.IX from an AAV vector in human subjects remains.;The second chapter of this dissertation details a follow up study on the initial muscle-directed, AAV-F.IX trial. We now show 10-year F.IX expression in the muscle of a trial subject. This is the longest expression yet demonstrated in humans from a parenterally administered gene therapy vector. While therapeutic levels were never achieved in this trial, the persistence of gene expression over a decade after vector administration is an important finding for the field of gene transfer.;Interestingly, AAV-F.IX delivery to the liver did result in efficacious levels of F.IX, but in the first human trial in liver, levels fell to baseline by two months post- delivery. The CD8 T cell response directed against the AAV capsid in these patients was not predicted in any pre-clinical animal studies. The third chapter of this dissertation investigates a uniquely human glycosylation mutation in the Cmah gene that potentially rendered humans more immunologically reactive. When modeled in mice, this mutation leads to enhanced T cell proliferation and activation in vitro, and to more robust T cell responses to viral challenges in vivo.;The goal of these investigations is to highlight the long-term potential of AAV-mediated gene transfer, while attempting to delineate the uniquely human immune mechanisms that that influence duration of expression and that were not predicted by extensive studies in other species.
机译：单基因人类疾病的成功基因转移可以潜在地提供单一治疗，终生治愈。然而，对于基因转移的安全性和有效性仍然存在担忧。腺相关病毒（AAV）是主要使用的非整合基因转移载体，可以在非分裂细胞中转导并持续存在，并且相对无炎症。 AAV已在B型血友病动物模型中取得了广泛的临床前成功，并在临床上获得了近期疗效。在因子IX（F.IX）的肌肉定向和肝定向基因转移中，在小鼠，犬和非人类灵长类动物中均观察到了来自AAV的F.IX多年表达。但是，通过肌肉定向转移至B型血友病受试者导致亚治疗性循环F.IX，而肝脏定向转移导致瞬时治疗性F.IX血浆水平被针对AAV的清除肝细胞的CD8 T细胞应答所消除衣壳。因此，维持人类受试者中AAV载体的F.IX长期，临床意义水平的挑战仍然存在。;本论文的第二章详细介绍了有关初始肌肉定向AAV-F.IX试验的后续研究。 。现在，我们在试验对象的肌肉中显示了10年的F.IX表达。这是通过肠胃外施用的基因治疗载体在人类中证实的最长的表达。尽管在该试验中从未达到治疗水平，但在载体给药后十年内基因表达的持久性是基因转移领域的重要发现。有趣的是，将AAV-F.IX递送至肝脏确实导致了有效水平的AAV-F。 F.IX，但在肝脏的首次人体试验中，分娩后两个月血脂水平降至基线。在任何临床前动物研究中均未预测到这些患者中针对AAV衣壳的CD8 T细胞应答。本论文的第三章研究了Cmah基因中一个独特的人类糖基化突变，它可能使人类具有更高的免疫反应性。当在小鼠中建模时，该突变导致体外T细胞增殖和活化增强，并在体内对病毒攻击产生更强大的T细胞反应。这些研究的目的是强调AAV介导的基因的长期潜力转移，同时试图描绘独特的人类免疫机制，这些机制会影响表达持续时间，而其他物种的广泛研究并未预测到这种免疫机制。

著录项

  • 作者

    Buchlis, George John.;

  • 作者单位

    University of Pennsylvania.;

  • 授予单位 University of Pennsylvania.;
  • 学科 Biology Molecular.;Biology Cell.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 147 p.
  • 总页数 147
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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