Gene therapy for human α1-antitrypsin deficiency in an animal model using SV40-derived vectors
Gene therapy for human α1-antitrypsin deficiency in an animal model using SV40-derived vectors
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DOI：
10.1053/j.gastro.2004.07.058
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发表时间：
2004-10-01
期刊：
影响因子：
29.4
通讯作者：
Zern, MA
中科院分区：
文献类型：
--
作者：
Duan, YY;Wu, J;Zern, MA
背景和目标：在大多数遗传性疾病中，基因治疗的目标是传递特定的转基因；然而，有时必须消除有害的基因产物。由于重组猿病毒 40 (rSV40) 载体的前景，我们通过将载体直接施用到人类 α(1)-抗胰蛋白酶 (α-AT) 缺乏症动物模型的肝脏来测试其传递转基因和靶向转录物以进行破坏的能力。方法：治疗人类 α(1)-AT 缺乏症需要稳定转导静息肝细胞，以传递野生型 (xi-AT) 并抑制突变型 α(1)-AT 的产生。携带突变型人类 α(1)-AT PiZ 等位基因的转基因小鼠通过留置门静脉导管，用源自猿猴病毒 40 (SV40) 的载体进行治疗，该载体携带旨在靶向人类转录物的核酶。结果：经过治疗的转基因小鼠显示出转导后3-16周，人α(1)-AT信使RNA和肝脏中的蛋白质显着减少，并且人油-AT的血清水平降低至治疗前值的50%+/-5%。此外，当用含有经过改造的人α(1)-AT互补DNA的SV40衍生载体处理以抵抗α(1)-AT核酶切割时，它们表达人α(1)-AT。他们的肝脏中的信使 RNA 和蛋白质以及人 α(1)-AT 的血清水平在一年内保持 > 1 微克/mL 结论：这些结果代表了针对 α(1)-AT 缺陷的基因治疗的新方法的初步步骤。
Background & Aims: In most genetic diseases, the goal of gene therapy is to deliver a particular transgene; however, sometimes a deleterious gene product must be eliminated. Because of the promise of recombinant simian virus 40 (rSV40) vectors, we tested their ability to deliver a transgene and to target a transcript for destruction by direct administration of the vectors to the liver of an animal model for human alpha(1)-antitrypsin (alpha-AT) deficiency. Methods: Therapy of human alpha(1)-AT deficiency requires stable transduction of resting hepatocytes, both to deliver wild-type (xi-AT and to inhibit production of mutant alpha(1)-AT. Transgenic mice carrying the mutant human alpha(1)-AT PiZ allele were treated through an indwelling portal vein catheter with a simian virus 40 (SV40)-derived vector carrying a ribozyme designed to target the human transcript. Results: Treated transgenic mice showed marked decreases of human alpha(1)-AT messenger RNA and the protein in the liver, and serum levels of human oil-AT were decreased to 50% +/- 5% of pretreatment values 3-16 weeks after transduction. Moreover, when normal mice were treated with an SV40-derived vector containing a modified human alpha(1)-AT complementary DNA engineered to be resistant to cleavage by the alpha(1)-AT ribozyme, they expressed human alpha(1)-AT messenger RNA and protein in their livers and serum levels of human alpha(1)-AT remained >1 mug/mL for 1 year. Conclusions: These results represent the initial steps toward a novel approach to the gene therapy of alpha(1)-AT deficiency.