A gene-deleted adenoviral vector results in phenotypic correction of canine hemophilia B without liver toxicity or thrombocytopenia
A gene-deleted adenoviral vector results in phenotypic correction of canine hemophilia B without liver toxicity or thrombocytopenia
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DOI：
10.1182/blood-2003-01-0314
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发表时间：
2003-10-01
期刊：
影响因子：
20.3
通讯作者：
Kay, MA
中科院分区：
文献类型：
--
作者：
Ehrhardt, A;Xu, H;Kay, MA
许多通过基因转移治疗血友病的方法已经在大型动物模型中进行了尝试，但都有潜在的缺点。重组腺病毒载体提供了一种高效的外泌体载体转移，但一直受到早期含有病毒基因的载体的细胞毒性/免疫原性的困扰。在我们目前的研究中，我们使用非整合辅助依赖（HD）腺病毒载体进行肝定向基因转移，以实现b型血友病犬的止血矫正。我们在治疗范围内测量了长达2.5个月的血浆犬因子IX （cFIX）浓度，并测量了大约一个月的全血凝固时间（WBCT）正常化。随后是4.5个月的下降和稳定的部分修正。稍低剂量的HD载体的肝脏基因转移导致wbts在2周内接近正常，表明在狗中存在剂量阈值效应。与使用第一代或第二代腺病毒载体的其他研究形成鲜明对比的是，我们观察到肝酶没有与载体相关的升高，血小板计数没有下降，肝脏组织学正常。综上所述，本研究表明，在犬模型中，腺病毒HD载体的注射导致FIX缺陷的完全但短暂的表型纠正，而没有可检测到的毒性。(C) 2003年由美国血液病学会出版。
Many approaches for treating hemophilia via gene transfer have been attempted in large animal models but all have potential drawbacks. Recombinant adenoviral vectors offer high-efficiency transfer of an episomal vector but have been plagued by the cytotoxicity/immunogenicity of early-generation vectors that contain viral genes. In our current study, we have used a nonintegrating helper-dependent (HD) adenoviral vector for liver-directed gene transfer to achieve hemostatic correction in a dog with hemophilia B. We measured plasma canine factor IX (cFIX) concentrations at a therapeutic range for up to 2.5 months and normalization of the whole blood clotting time (WBCT) for about a month. This was followed by a decrease and stabilized partial correction for 4.5 months. Hepatic gene transfer of a slightly lower dose of the HD vector resulted in WBCTs that were close to normal for 2 weeks, suggesting a dose threshold effect in dogs. In sharp contrast to other studies using first- or second-generation adenoviral vectors, we observed no vector-related elevation of liver enzymes, no fall in platelet counts, and normal liver histology. Taken together, this study demonstrates that injection of an adenoviral HD vector results in complete but transient phenotypic correction of FIX deficiency in canine models with no detectable toxicity. (C) 2003 by The American Society of Hematology.