SERPINA1 mRNA as a Treatment for Alpha-1 Antitrypsin Deficiency.
SERPINA1 mRNA as a Treatment for Alpha-1 Antitrypsin Deficiency.
复制标题
DOI：
10.1155/2018/8247935
复制
发表时间：
2018
影响因子：
2.3
通讯作者：
Subramanian RR
中科院分区：
文献类型：
--
作者：
Connolly B;Isaacs C;Cheng L;Asrani KH;Subramanian RR
α-1-抗胰蛋白酶(AAT)缺乏是一种遗传性疾病，由于编码AAT的SERPINA1基因突变而产生不活跃/缺陷的AAT。这种疾病与肺中AAT活性降低和肝脏中过多的缺陷AAT蛋白沉积有关。目前还没有针对与AAT缺乏相关的肝病的特效治疗方法。AAT肺病通常使用几种血清蛋白替代产品中的一种来治疗；然而，没有关于SERPINA1替代疗法有效性的长期研究，而且它不能减少AAT缺乏时的肝脏损害。基因治疗有可能同时针对AAT缺乏患者的肝脏和肺。将编码SERPINA1基因的mRNA导入AAT患者成纤维细胞和AAT患者成纤维细胞来源的肝细胞，并检测细胞培养液中SERPINA1的表达。我们的数据显示，AAT患者成纤维细胞和AAT患者成纤维细胞来源的肝细胞培养上清液中的SERPINA1蛋白增加。在野生型小鼠体内的研究表明，SERPINA1 mRNA在肝脏和肺中的生物分布以及SERPINA1蛋白在这两个受AAT缺乏严重影响的靶器官中的表达。综上所述，我们的数据表明，SERPINA1基因治疗有可能使AAT缺乏症患者受益。
Alpha-1-antitrypsin (AAT) deficiency is a genetic disorder that produces inactive/defective AAT due to mutations in the SERPINA1 gene encoding AAT. This disease is associated with decreased activity of AAT in the lungs and deposition of excessive defective AAT protein in the liver. Currently there is no specific treatment for liver disease associated with AAT deficiency. AAT lung disease is often treated with one of several serum protein replacement products; however, long-term studies of the effectiveness of SerpinA1 replacement therapy are not available, and it does not reduce liver damage in AAT deficiency. mRNA therapy could potentially target both the liver and lungs of AAT deficient patients. AAT patient fibroblasts and AAT patient fibroblast-derived hepatocytes were transfected with SERPINA1-encoding mRNA and cell culture media were tested for SerpinA1 expression. Our data demonstrates increased SerpinA1 protein in culture media from treated AAT patient fibroblasts and AAT patient fibroblast-derived hepatocytes. In vivo studies in wild type mice demonstrate SERPINA1 mRNA biodistribution in liver and lungs, as well as SerpinA1 protein expression in these two target organs which are critically affected in AAT deficiency. Taken together, our data suggests that SerpinA1 mRNA therapy has the potential to benefit patients suffering from AAT deficiency.