Safety and feasibility of liver-directed ex vivo gene therapy for homozygous familial hypercholesterolemia
Safety and feasibility of liver-directed ex vivo gene therapy for homozygous familial hypercholesterolemia
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DOI：
10.1097/00000658-199602000-00002
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发表时间：
1996-02-01
影响因子：
9
通讯作者：
Wilson, JM
中科院分区：
文献类型：
--
作者：
Raper, SE;Grossman, M;Wilson, JM
这份报告的目的是提供详细的信息，与第一个体外肝脏定向基因治疗试验治疗家族性高胆固醇血症（FH）的安全性和可行性的外科手术。摘要背景资料家族性高胆固醇血症是一种常染色体显性遗传疾病，其中编码低密度脂蛋白受体的基因是有缺陷的。这种突变的纯合子患者胆固醇水平异常高，动脉粥样硬化加速，并过早死于心肌梗死。肝脏定向基因治疗的概念是基于报告的胆固醇水平正常化原位心脏/肝脏移植在一个孩子与纯合子FH.MethodsFive纯合子FH患者入选本试验。患者接受了肝切除术和门静脉导管放置。从切除的肝脏制备原代肝细胞培养物，并用编码人低密度脂蛋白受体基因的重组逆转录病毒转导。转基因细胞，然后移植到肝脏通过门静脉catheters. ResultsMany临床，实验室和放射学参数进行了分析。观察到肝转氨酶和白细胞计数升高以及红细胞压积计数下降。在细胞输注期间观察到门静脉压力的短暂升高。没有重大的围手术期发病率，特别是心肌梗死，围手术期出血，或门静脉血栓形成或死亡发生作为结果，本protocol. ConclusionLiver定向体外基因治疗可以安全地完成在人类中，是适合于选定的患者。
ObjectiveThe purpose of this report was to provide detailed information on the safety and feasibility of surgical procedures associated with the first ex vivo liver-directed gene therapy trial for the treatment of familial hypercholesterolemia (FH).Summary Background DataFamilial hypercholesterolemia is an autosomal dominant disease in which the gene encoding the low density lipoprotein receptor is defective. Patients homozygous for this mutation have extraordinarily high levels of cholesterol and accelerated atherosclerosis and die prematurely of myocardial infarction. The concept of liver-directed gene therapy was based on the report of normalization of cholesterol levels by orthotopic cardiac/liver transplant in a child with homozygous FH.MethodsFive patients with homozygous FH were selected for inclusion in this trial. The patients underwent hepatic resection and placement of a portal venous catheter. Primary hepatocytes cultures were prepared from the resected liver and transduced with a recombinant retrovirus encoding the gene for the human low density lipoprotein receptor. The genetically modified cells were then transplanted into the liver through the portal venous catheter.ResultsNumerous clinical, laboratory, and radiologic parameters were analyzed. Elevations of the hepatic transaminases and leukocyte counts and a decline in hematocrit count were noted. Transient elevations of the portal pressure were observed during cell infusion. No major perioperative morbidity-specifically, myocardial infarct, perioperative hemorrhage, or portal vein thrombosis-or death occurred as a result of this protocol.ConclusionLiver-directed ex vivo gene therapy can be accomplished safely in humans and is appropriate for selected patients.