Connolly Brendan, Isaacs Cleo, Cheng Lei, Asrani Kirtika H, Subramanian Romesh R
Alexion Pharmaceuticals Inc., 75 Sidney St, Cambridge, MA 02139, USA.
J Nucleic Acids. 2018 Jun 13;2018:8247935. doi: 10.1155/2018/8247935. eCollection 2018.
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.
α-1抗胰蛋白酶（AAT）缺乏症是一种遗传性疾病，由于编码AAT的SERPINA1基因突变，导致产生无活性/有缺陷的AAT。这种疾病与肺部AAT活性降低以及肝脏中过量有缺陷的AAT蛋白沉积有关。目前，尚无针对与AAT缺乏相关的肝病的特异性治疗方法。AAT肺病通常用几种血清蛋白替代产品之一进行治疗；然而，关于丝氨酸蛋白酶抑制剂A1替代疗法有效性的长期研究尚不可得，并且它不能减轻AAT缺乏症患者的肝损伤。mRNA疗法有可能针对AAT缺乏患者的肝脏和肺部。用编码SERPINA1的mRNA转染AAT患者成纤维细胞和AAT患者成纤维细胞衍生的肝细胞，并检测细胞培养基中的丝氨酸蛋白酶抑制剂A1表达。我们的数据表明，来自经处理的AAT患者成纤维细胞和AAT患者成纤维细胞衍生的肝细胞的培养基中丝氨酸蛋白酶抑制剂A1蛋白增加。在野生型小鼠中进行的体内研究表明，SERPINA1 mRNA在肝脏和肺部的生物分布，以及在这两个在AAT缺乏症中受到严重影响的靶器官中的丝氨酸蛋白酶抑制剂A1蛋白表达。综上所述，我们的数据表明，丝氨酸蛋白酶抑制剂A1 mRNA疗法有可能使AAT缺乏症患者受益。
