McLean Caitriona, Greene Catherine M, McElvaney Noel G
Respiratory Research Division, Dept. Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
Biologics. 2009;3:63-75. Epub 2009 Jul 13.
Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys). ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs) and RNA interference (RNAi), which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.
α-1抗胰蛋白酶（A1AT）是一种52 kDa的丝氨酸蛋白酶抑制剂，在肝脏中合成并分泌。尽管它存在于身体的所有组织中，但目前的共识是其主要作用是抑制肺部的中性粒细胞弹性蛋白酶。A1AT缺乏症是由于A1AT基因突变导致血清A1AT水平降至正常水平的<35%。A1AT缺乏症最具临床意义的形式是由Z突变（Glu342Lys）引起的。ZA1AT在肝细胞内质网中聚合，突变蛋白的积累会导致肝脏疾病，而循环中A1AT的减少会导致肺部疾病，包括早发性肺气肿。目前除了移植外，尚无针对肝脏疾病的有效治疗方法，针对该疾病肺部表现的治疗方法仍然有限。基因治疗是一个不断发展的领域，可能作为治疗A1AT缺乏症的一种方法。由于与A1AT缺乏症相关的肝脏疾病可能代表功能获得，针对这种情况的可能基因治疗包括使用核酶、肽核酸（PNA）和RNA干扰（RNAi），通过减少细胞中异常蛋白的量，可能会影响该疾病的发病机制。
