Liver-directed SERPINA1 gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice.
Liver-directed SERPINA1 gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice.
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DOI：
10.1016/j.omtm.2022.04.003
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发表时间：
2022-06-09
期刊：
影响因子：
--
通讯作者：
Mueller, Christian
中科院分区：
文献类型：
--
作者：
Zieger, Marina;Borel, Florie;Greer, Cynthia;Gernoux, Gwladys;Blackwood, Meghan;Flotte, Terence R.;Mueller, Christian
α1-抗胰蛋白酶缺乏症是一种罕见的遗传性疾病，可导致肝脏和/或肺部疾病。目前还没有治愈这种疾病的方法，尽管反复输注血浆纯化蛋白可能会减缓肺气肿的进展。基因治疗，其中一个单一的重组腺相关病毒载体（rAAV）管理将导致持续的蛋白质表达，因此可以类似地影响疾病的进展，并提供额外的好处，减少治疗负担，从而提高患者的生活质量。本研究测试了用基因疗法治疗α1-抗胰蛋白酶缺乏性肺病的Serpina 1a-e敲除小鼠模型是否会对疾病进程产生影响，无论是对衰老引起的自发性疾病还是对暴露于香烟烟雾引起的加速性疾病。肝脏定向基因治疗导致生物活性人α1-抗胰蛋白酶蛋白的剂量依赖性水平。此外，肺顺应性降低和弹性回缩增加表明，与未处理的小鼠相比，处理的小鼠在很大程度上保留了肺组织弹性和肺泡壁完整性。因此，rAAV介导的基因扩增能够补偿功能丧失并恢复有益的肺蛋白酶-抗蛋白酶平衡。这项工作构成了临床前研究报告的疾病修饰治疗的Serpina 1a-e敲除小鼠模型使用肝脏特异性rAAV血清型8衣壳。肝脏导向的SERPINA 1基因增强治疗弥补了α1-抗胰蛋白酶（AAT）蛋白的损失。小鼠肝脏分泌的人AAT蛋白具有完全的生物化学活性，并有效地抑制中性粒细胞弹性蛋白酶。在AAT缺乏的Serpina 1a-e基因敲除小鼠模型中，恢复的蛋白酶-抗蛋白酶平衡保护肺实质并保留肺功能。
α1-antitrypsin deficiency is a rare genetic condition that can cause liver and/or lung disease. There is currently no cure for this disorder, although repeated infusions of plasma-purified protein may slow down emphysema progression. Gene therapy in which a single recombinant adeno-associated viral vector (rAAV) administration would lead to sustained protein expression could therefore similarly affect disease progression, and provide the added benefits of reducing treatment burden and thereby improving the patient’s quality of life. The study presented here tests whether treating the Serpina1a-e knockout mouse model of α1-antitrypsin-deficiency lung disease with gene therapy would have an impact on the disease course, either on spontaneous disease caused by aging or on accelerated disease caused by exposure to cigarette smoke. Liver-directed gene therapy led to dose-dependent levels of biologically active human α1-antitrypsin protein. Furthermore, decreased lung compliance and increased elastic recoil indicate that treated mice had largely preserved lung tissue elasticity and alveolar wall integrity compared with untreated mice. rAAV-mediated gene augmentation is therefore able to compensate for the loss of function and restore a beneficial lung protease-antiprotease balance. This work constitutes a preclinical study report of a disease-modifying treatment in the Serpina1a-e knockout mouse model using a liver-specific rAAV serotype 8 capsid. Liver-directed SERPINA1 gene augmentation therapy compensates for the loss of α1-antitrypsin (AAT) protein. Mouse liver-secreted human AAT protein is fully biochemically active and effectively inhibits neutrophil elastase. The restored protease-antiprotease balance protects lung parenchyma and preserves pulmonary function in the Serpina1a-e knockout mouse model of AAT deficiency.
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影响因子：
15.9
作者：
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通讯作者：
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