Pulmonary vasculature directed adenovirus increases epithelial lining fluid alpha-1 antitrypsin levels.
Pulmonary vasculature directed adenovirus increases epithelial lining fluid alpha-1 antitrypsin levels.
复制标题
肺血管系统定向腺病毒增加上皮衬里液 α-1 抗胰蛋白酶水平。
DOI：
10.1002/jgm.2874
复制
发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Curiel,DavidT
中科院分区：
文献类型：
--
作者：
Buggio,Maurizio;Towe,Christopher;Annan,Anand;Kaliberov,Sergey;Lu,ZhiHong;Stephens,Calvin;Arbeit,JeffreyM;Curiel,DavidT
背景遗传性血清缺乏性疾病的基因治疗以前一直受到获得足够表达和引起肝脏毒性之间的平衡的限制。在本研究中，我们使用改良的肺靶向腺病毒在C57BL/6 J小鼠中表达人α1抗胰蛋白酶(A1AT)。结果使用靶向腺病毒，我们能够在较少的肝脏病毒摄取的情况下获得类似的血清A1AT水平的升高。我们还在小鼠模型中增加了肺上皮细胞衬里液A1AT水平，与表达A1AT的非靶向腺病毒相比增加了一个数量级以上。在取得这些成果的同时，有证据表明全身炎症减少，没有证据表明载体靶向末端器官内的炎症增加。结论除了向临床可行的A1AT基因治疗迈进一步外，作用部位蛋白质产量的最大化代表着系统传递的肺靶向基因治疗领域的一项重大技术进步。它还提供了一种替代以往肝脏病毒转导和相关毒性的局限性。版权所有©2016 John Wiley&Sons，Ltd.
BackgroundGene therapy for inherited serum deficiency disorders has previously been limited by the balance between obtaining adequate expression and causing hepatic toxicity. Our group has previously described modifications of a replication deficient human adenovirus serotype 5 that increase pulmonary vasculature transgene expression.MethodsIn the present study, we use a modified pulmonary targeted adenovirus to express human alpha‐1 antitrypsin (A1AT) in C57BL/6 J mice.ResultsUsing the targeted adenovirus, we were able to achieve similar increases in serum A1AT levels with less liver viral uptake. We also increased pulmonary epithelial lining fluid A1AT levels by more than an order of magnitude compared to that of untargeted adenovirus expressing A1AT in a mouse model. These gains are achieved along with evidence of decreased systemic inflammation and no evidence for increased inflammation within the vector‐targeted end organ.ConclusionsIn addition to comprising a step towards clinically viable gene therapy for A1AT, maximization of protein production at the site of action represents a significant technical advancement in the field of systemically delivered pulmonary targeted gene therapy. It also provides an alternative to the previous limitations of hepatic viral transduction and associated toxicities. Copyright © 2016 John Wiley & Sons, Ltd.