Using antisense technology to develop a novel therapy for α-1 antitrypsin deficient (AATD) liver disease and to model AATD lung disease
Using antisense technology to develop a novel therapy for α-1 antitrypsin deficient (AATD) liver disease and to model AATD lung disease
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使用反义技术开发α-1抗胰蛋白酶缺乏（AATD）肝病的新疗法并模拟AATD肺病
DOI：
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
B. Monia
中科院分区：
文献类型：
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作者：
Shuling Guo;S. Booten;A. Watt;Luis Alvarado;S. Freier;J. Teckman;M. McCaleb;B. Monia
α-1抗胰蛋白酶（AAT）是一种血清蛋白酶抑制剂，属于丝氨酸蛋白酶抑制剂超家族。AAT突变与α-1抗胰蛋白酶缺乏症（AATD）相关，AATD是一种罕见的遗传性疾病，有两种不同的表现：AATD肺病和AATD肝病。AATD肺病是由AAT功能丧失引起的，可以用血浆来源的AAT治疗。AATD肝病是由于突变型AAT蛋白在肝脏中的聚集和保留; AATD肝病的唯一治疗方法是肝移植。在这里，我们证明了靶向人AAT的反义寡核苷酸（ASO）在体外和转基因小鼠中有效地降低了短和长人AAT转录物的水平，为AATD肝病提供了一种新的治疗方法。此外，ASO介导的小鼠AAT耗竭可能为研究AATD肺病提供有用的动物模型。
Alpha-1 antitrypsin (AAT) is a serum protease inhibitor that belongs to the serpin superfamily. Mutations in AAT are associated with α-1 antitrypsin deficiency (AATD), a rare genetic disease with two distinct manifestations: AATD lung disease and AATD liver disease. AATD lung disease is caused by loss-of-function of AAT and can be treated with plasma-derived AAT. AATD liver disease is due to the aggregation and retention of mutant AAT protein in the liver; the only treatment available for AATD liver disease is liver transplantation. Here we demonstrate that antisense oligonucleotides (ASOs) targeting human AAT efficiently reduce levels of both short and long human AAT transcript in vitro and in transgenic mice, providing a novel therapy for AATD liver disease. In addition, ASO-mediated depletion of mouse AAT may offer a useful animal model for the investigation of AATD lung disease.