Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy.
Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy.
复制标题
甲型血友病犬接受肝脏定向新生儿基因治疗后，治疗性表达因子 VIII 后缺乏去氨加压素反应。
DOI：
10.1073/pnas.0409249102
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发表时间：
2005
影响因子：
11.1
通讯作者：
Ponder,KatherineP
中科院分区：
文献类型：
--
作者：
Xu,Lingfei;Nichols,TimothyC;Sarkar,Rita;McCorquodale,Stephanie;Bellinger,DwightA;Ponder,KatherineP
血友病A（HA）是由凝血因子VIII（FVIII）缺乏引起的出血性疾病。FVIII替代疗法可以减少出血，但昂贵、不方便，并且由于在30%的患者中产生抑制FVIII活性的抗体而变得复杂。新生儿肝脏基因治疗可导致FVIII持续分泌入血，并可能降低免疫反应。静脉注射表达犬B结构域缺失FVIII（cFVIII）的逆转录病毒载体（RV）的新生HA小鼠和犬，其血浆cFVIII活性分别为正常犬的139 ± 22%和116 ± 5%，可稳定1.5年。凝血试验正常化，未发生出血，未检测到抑制物。这是在大型动物模型中对HA的长期完全治疗性基因疗法的证明。去氨加压素（DDAVP; 1-脱氨基-[d-Arg 8]加压素）是一种通过诱导与血管性血友病因子复合的FVIII从内皮细胞释放来增加FVIII活性的药物。然而，目前还不清楚FVIII是由内皮细胞合成还是从血液中摄取。由于这些RV给药犬的血浆cFVIII主要来源于转导的肝细胞，因此为研究DDAVP反应的生物学提供了独特的机会。在这里，我们表明DDAVP没有增加RV治疗犬的血浆cFVIII水平，尽管血管性血友病因子适当增加。该结果表明，DDAVP后正常犬中FVIII的增加是由于内皮细胞合成的FVIII的释放。
Hemophilia A (HA) is a bleeding disorder caused by factor VIII (FVIII) deficiency. FVIII replacement therapy can reduce bleeding but is expensive, inconvenient, and complicated by development of antibodies that inhibit FVIII activity in 30% of patients. Neonatal hepatic gene therapy could result in continuous secretion of FVIII into blood and might reduce immunological responses. Newborn HA mice and dogs that were injected i.v. with a retroviral vector (RV) expressing canine B domain-deleted FVIII (cFVIII) achieved plasma cFVIII activity that was 139 ± 22% and 116 ± 5% of values found in normal dogs, respectively, which was stable for 1.5 yr. Coagulation tests were normalized, no bleeding had occurred, and no inhibitors were detected. This is a demonstration of long-term fully therapeutic gene therapy for HA in a large animal model. Desmopressin (DDAVP; 1-deamino-[d-Arg8]vasopressin) is a drug that increases FVIII activity by inducing release of FVIII complexed with von Willebrand factor from endothelial cells. It has been unclear, however, if the FVIII is synthesized by endothelial cells or is taken up from blood. Because the plasma cFVIII in these RV-treated dogs derives primarily from transduced hepatocytes, they provided a unique opportunity to study the biology of the DDAVP response. Here we show that DDAVP did not increase plasma cFVIII levels in the RV-treated dogs, although von Willebrand factor was increased appropriately. This result suggests that the increase in FVIII in normal dogs after DDAVP is due to release of FVIII synthesized by endothelial cells.