Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy.
Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy.
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逆转录病毒载体介导的肝基因治疗后大鼠体内人蛋白 C 的治疗水平。
DOI：
10.1172/jci1880
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Ponder,KP
中科院分区：
文献类型：
--
作者：
Cai,SR;Kennedy,SC;Bowling,WM;Flye,MW;Ponder,KP
蛋白C缺乏导致血栓形成障碍，可能通过在患者中表达正常的人蛋白C （hPC）基因来治疗。在肝脏再生过程中，将一种具有肝脏特异性启动子和hPC cDNA的两性性逆转录病毒载体在体内传递给大鼠肝细胞。hPC在转导后2周的表达范围为55 ~ 203ng /ml（正常值的1.3 ~ 5.0%）。在一些大鼠中，表达量平均增加到900 ng/ml（正常水平的22%），并在1年内保持稳定水平。所有这些大鼠都产生了抗hPC抗体，并表现出较长的hPC半衰期。免疫沉淀后，通过显色底物试验确定hPC具有功能。我们的结论是，大多数大鼠的hPC水平可以预防暴发性紫癜，肝脏基因治疗可能成为严重纯合子hPC缺乏症患者的可行治疗方法。抗hPC抗体在一些大鼠中增加了hPC半衰期和血浆水平，但不干扰其功能活性。因此，在基因治疗实验中，针对血浆蛋白的抗体的发展并不一定会取消其生物学效应。
Protein C deficiency results in a thrombotic disorder that might be treated by expressing a normal human protein C (hPC) gene in patients. An amphotropic retroviral vector with a liver-specific promoter and the hPC cDNA was delivered to rat hepatocytes in vivo during liver regeneration. Expression of hPC varied from 55 to 203 ng/ml (1.3-5.0% of normal) for 2 wk after transduction. Expression increased to an average of 900 ng/ml (22% of normal) in some rats and was maintained at stable levels for 1 yr. All of these rats developed anti-hPC antibodies and exhibited a prolonged hPC half-life in vivo. The hPC was functional as determined by a chromogenic substrate assay after immunoprecipitation. We conclude that most rats achieved hPC levels that would prevent purpura fulminans, and that hepatic gene therapy might become a viable treatment for patients with severe homozygous hPC deficiency. Anti-hPC antibodies increased the hPC half-life and plasma levels in some rats, but did not interfere with its functional activity. Thus, the development of antibodies against a plasma protein does not necessarily abrogate its biological effect in gene therapy experiments.