Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity.
Adenovirus-mediated expression of human coagulation factor IX in the rhesus macaque is associated with dose-limiting toxicity.
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恒河猴中腺病毒介导的人凝血因子 IX 表达与剂量限制性毒性相关。
作者：
Jay N. Lozier;M. Metzger;Robert E. Donahue;Richard A. Morgan
我们使用第一代腺病毒载体（AVC 3FIX 5）来评估是否可以在恒河猴中表达和检测到人因子IX，我们已经证明这不会产生针对人因子IX蛋白的高滴度抗体。3只动物通过静脉注射接受1 × 10（10）至1 × 10（11）个空斑形成单位/kg。人因子IX在载体给药后24小时内存在，4天后在高剂量接受者中达到峰值，为4，000 ng/mL，在中等剂量接受者中观察到较低水平。在低剂量受体血浆中未检测到人因子IX。血清细胞因子分析和早期低铁血症提示对载体的剂量依赖性急性期反应。人因子IX在恒河猴血浆中可检测到2至3周的高剂量和中等剂量受体，但消失伴随着高滴度抗人因子IX抗体的发展。存在大量剂量依赖性、剂量限制性肝毒性，表现为血清转氨酶水平升高、高胆红素血症、低白蛋白血症和凝血时间延长。特别令人感兴趣的是凝血酶凝固时间的延长，这是纤维蛋白原减少或纤维蛋白原功能障碍的指标。除了高剂量接受者出现持续性低纤维蛋白原血症外，所有肝脏毒性证据均已消退，这表明可能存在永久性肝脏损伤。我们的数据表明，第一代腺病毒介导的基因转移的治疗窗口很窄。恒河猴中抗人因子IX抗体和纤维蛋白原异常的发展是将腺病毒（或其他病毒）载体应用于血友病基因治疗的关注点。
We used a first-generation adenovirus vector (AVC3FIX5) to assess whether human factor IX could be expressed and detected in the rhesus macaque, which we have shown does not make high-titer antibodies to human factor IX protein. Three animals received 1 x 10(10) to 1 x 10(11) plaque-forming units per kilogram by intravenous injection. Human factor IX was present within 24 hours of vector administration and peaked 4 days later at 4,000 ng/mL in the high-dose recipient, and lower levels were seen in the intermediate-dose recipient. No human factor IX was detected in the low-dose recipient's plasma. Serum cytokine analysis and early hypoferremia suggested a dose-dependent acute-phase response to the vector. Human factor IX was detectable in rhesus plasma for 2 to 3 weeks for the high- and intermediate-dose recipients, but disappeared concomitant with high-titer antihuman factor IX antibody development. There was substantial, dose-dependent, dose-limiting liver toxicity that was manifest as elevated serum transaminase levels, hyperbilirubinemia, hypoalbuminemia, and prolongation of clotting times. Of particular interest was prolongation of the thrombin clotting time, an indicator of decreased fibrinogen or fibrinogen dysfunction. All evidence of liver toxicity resolved except for persistent hypofibrinogenemia in the high-dose recipient, indicating possible permanent liver damage. Our data suggest a narrow therapeutic window for first-generation adenovirus-mediated gene transfer. The development of antihuman factor IX antibodies and abnormalities of fibrinogen in the rhesus macaque is of concern for application of adenovirus (or other viral) vectors to hemophilia gene therapy.
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肌内注射复制缺陷型腺病毒载体后，啮齿动物和非人灵长类动物中促红细胞生成素的长期表达。
DOI：
10.1089/hum.1997.8.15-1797
发表时间：
1997
期刊：
Human gene therapy.
影响因子：
--
作者：
Svensson,EC;Black,HB;Dugger,DL;Tripathy,SK;Goldwasser,E;Hao,Z;Chu,L;Leiden,JM
通讯作者：
Leiden,JM
含有温度敏感 E2A 突变的 E1 重组腺病毒载体在免疫活性小鼠和 B 型血友病犬中缺乏持久性。
DOI：
--
发表时间：
1996
期刊：
Gene therapy.
影响因子：
--
作者：
Fang,B;Wang,H;Gordon,G;Bellinger,DA;Read,MS;Brinkhous,KM;Woo,SL;Eisensmith,RC
通讯作者：
Eisensmith,RC
腺病毒介导的免疫缺陷和正常小鼠中人类因子 IX 基因的转移：转基因在肝脏中的长期稳定性和活性的证据。
DOI：
10.1089/vim.1996.9.141
发表时间：
1996
期刊：
Viral immunology.
影响因子：
--
作者：
Yao,SN;Farjo,A;Roessler,BJ;Davidson,BL;Kurachi,K
通讯作者：
Kurachi,K
影响因子：
3.7
作者：
Hu, Shengwei;Ni, Wei;Chen, Chuangfu
通讯作者：
Chen, Chuangfu
在小鼠中重复施用腺病毒载体后成功表达人因子 IX。
DOI：
10.1073/pnas.93.7.3056
发表时间：
1996
影响因子：
11.1
作者：
Walter,J;You,Q;Hagstrom,JN;Sands,M;High,KA
通讯作者：
High,KA