Phenotype correction of hemophilia A mice with adeno-associated virus vectors carrying the B domain-deleted canine factor VIII gene
Phenotype correction of hemophilia A mice with adeno-associated virus vectors carrying the B domain-deleted canine factor VIII gene
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DOI：
10.1016/j.thromres.2005.11.006
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发表时间：
2006-01-01
影响因子：
7.5
通讯作者：
Sakata, Yoichi
中科院分区：
文献类型：
--
作者：
Ishiwata, Akira;Mimuro, Jun;Sakata, Yoichi
开发了携带 B 结构域缺失的犬 FVIII (BDD cFVIII) 基因的腺相关病毒 (AAV) 载体，该载体利用用血清型 1 (AAV1-beta-actin-cFVIII) 和血清型 8 (AAV8-beta-actin-cFVIII) 假型化的 β-肌动蛋白最小启动子 (167b) 来表达 A 型血友病小鼠中的 cFVIII。肌内注射 AAV1-β-actin-cFVIII 的 A 型血友病小鼠中，通过 APTT 方法测得的 FVIII 凝血活性呈剂量依赖性增加。使用 1x10(12) gc/体的 AAV1-β-肌动蛋白-cFVIII 剂量的 AAV1-β-肌动蛋白-cFVIII 血友病 A 小鼠中实现了治疗性 FVIII 水平 (2.9 +/- 1.0%)，表明用 AAV1-β-肌动蛋白-cFVIII 载体部分校正了表型。静脉注射 AAV8-β-肌动蛋白-cFVIII 的血友病 A 小鼠中的 FVIII 凝血活性水平也呈剂量依赖性增加，在 AAV8-β-肌动蛋白-cFVIII 剂量为 1-3 x 10(11) gc/体的血友病 A 小鼠中达到治疗性 FVIII 水平 (5-90%) 和超常 AAV8-β-肌动蛋白-cFVIII 剂量为 1 x 10(12) gc/体的血友病 A 小鼠中的 FVIII 水平 (180-670%)。在 FVIII 产生和抗体形成方面，用 AAV8-β-肌动蛋白-cFVIII 转导肝脏优于用 AAV1cFVIII 转导骨骼肌。这些数据表明，利用最小启动子携带FVIII基因的AM和AAV8载体都具有用于血友病A基因治疗的潜力。 (c) 2005 Elsevier Ltd. 保留所有权利。
Adeno-associated virus (AAV) vectors carrying the B domain-deleted canine FVIII (BDD cFVIII) gene utilizing the beta-actin minimum promoter (167b) pseudotyped with serotype 1 (AAV1-beta-actin-cFVIII) and serotype 8 (AAV8-beta-actin-cFVIII) were developed to express cFVIII in hemophilia A mice. FVIII clotting activities measured by the APTT method increased in hemophilia A mice with intramuscular injection of AAV1-beta-actin-cFVIII in a dose-dependent manner. Therapeutic FVIII levels (2.9 +/- 1.0%) in hemophilia A mice with the AAV1-beta-actin-cFVIII dose of 1x10(12) gc/body were achieved, suggesting partial correction of the phenotype with AAV1-beta-actin-cFVIII vectors. FVIII clotting activity levels in hemophilia A mice with intravenous injection of AAV8-beta-actin-cFVIII also were increased dose-dependently, achieving therapeutic FVIII levels (5-90%) in hemophilia A mice with the AAV8-beta-actin-cFVIII doses of 1-3 x 10(11) gc/body and supernormal FVIII levels (180-670%) in hemophilia A mice with the AAV8-beta-actin-cFVIII dose of 1 x 10(12) gc/body. Transduction of the liver with AAV8-beta-actin-cFVIII is superior to transduction of skeletal muscles with AAV1cFVIII regarding the FVIII production and antibody formation. These data suggested that both AM and AAV8 vectors carrying the FVIII gene utilizing a minimum promoter have a potential for hemophilia A gene therapy. (c) 2005 Elsevier Ltd. All rights reserved.