Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1
Safety and efficacy of factor IX gene transfer to skeletal muscle in murine and canine hemophilia B models by adeno-associated viral vector serotype 1
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DOI：
10.1182/blood-2003-05-1446
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发表时间：
2004-01-01
期刊：
影响因子：
20.3
通讯作者：
High, KA
中科院分区：
文献类型：
--
作者：
Arruda, VR;Schuettrumpf, J;High, KA
腺相关病毒 (AAV) 载体（血清型 2）可有效转导骨骼肌，并已被用作实验动物和人类的血友病 B 和肌营养不良症的基因递送载体。最近的报告表明，基于血清型 1、5 和 7 的 AAV 载体比 AAV-2 更有效地转导小鼠骨骼肌，据报道表达量增加了 2 倍至 1000 倍。我们试图确定这种功效的增加是否可以在小鼠以外的物种中观察到。在免疫缺陷小鼠中，我们在一定剂量范围内观察到人类因子 IX (hF.IX) 表达水平高出 10 至 20 倍，而在血友病犬中，我们观察到表达水平高出约 50 倍。转基因表达的增加部分是由于更高的基因拷贝数和每个注射位点转导的细胞数量更多。在所有注射 AAV-1 的免疫功能正常的动物中，都会产生 F.IX 的抑制性抗体，但在接受高剂量载体治疗的免疫功能正常的小鼠中，抑制性抗体最终消失。这些研究强调，AAV-1 载体功效的增加存在形成抑制剂的风险，需要进一步研究来确定导致 F.IX 耐受而非免疫的剂量和治疗方案。
Adeno-associated viral (AAV) vectors (serotype 2) efficiently transduce skeletal muscle, and have been used as gene delivery vehicles for hemophilia B and for muscular dystrophies in experimental animals and humans. Recent reports suggest that AAV vectors based on serotypes 1, 5, and 7 transduce murine skeletal muscle much more efficiently than AAV-2, with reported increases in expression ranging from 2-fold to 1000-fold. We sought to determine whether this increased efficacy could be observed in species other than mice. In Immunodeficient mice we saw 10- to 20-fold higher levels of human factor IX (hF.IX) expression at a range of doses, and in hemophilic dogs we observed approximately 50-fold higher levels of expression. The increase in transgene expression was due partly to higher gene copy number and a larger number of cells transduced at each injection site. In all immunocompatent animals injected with AAV-1, inhibitory antibodies to F.IX developed, but in immunocompetent mice treated with high doses of vector, inhibitory antibodies eventually disappeared. These studies emphasize that the increased efficacy of AAV-1 vectors carries a risk of inhibitor formation, and that further studies will be required to define doses and treatment regimens that result in tolerance rather than immunity to F.IX.