Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema.
Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema.
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DOI：
10.1073/pnas.1713689115
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发表时间：
2018-03-13
影响因子：
11.1
通讯作者：
Mueller C
中科院分区：
文献类型：
--
作者：
Borel F;Sun H;Zieger M;Cox A;Cardozo B;Li W;Oliveira G;Davis A;Gruntman A;Flotte TR;Brodsky MH;Hoffman AM;Elmallah MK;Mueller C
慢性阻塞性肺疾病影响着全球 10% 的人口，其主要遗传原因是遗传性疾病 α-1 抗胰蛋白酶 (AAT) 缺乏症。人类只有一个编码 AAT 蛋白的基因，但小鼠有多达六个基因，这使得几十年来一直无法建立这种疾病的小鼠模型。在这里，我们使用 CRISPR 技术成功创建了这种小鼠模型，一次性靶向所有小鼠基因。重要的是，这种小鼠模型自发地患上肺部疾病，并概括了人类疾病的许多方面。我们预计该模型不仅与 AAT 缺乏疗法的临床前开发高度相关，而且与肺气肿和吸烟研究高度相关。慢性阻塞性肺疾病影响着全球 10% 的人口，其主要原因是 α-1 抗胰蛋白酶 (AAT) 缺乏。由于小鼠基因座的复杂性，其中包括多达六个 Serpina1 旁系同源物，迄今为止尚未成功产生该疾病的遗传动物模型。在这里，我们使用 CRISPR/Cas9 介导的基因组编辑创建了五重 Serpina1a-e 敲除。该表型概括了人类疾病表型，即肝脏和循环 AAT 的缺乏在功能上转化为抑制中性粒细胞弹性蛋白酶的能力降低。随着年龄的增长，Serpina1缺失小鼠会自发出现肺气肿，这可以通过脂多糖攻击在年轻小鼠中诱导。这种小鼠不仅可以模拟 AAT 缺乏症，还可以模拟肺气肿，并且是一种相关的遗传模型，而不是基于肺泡化或弹性蛋白酶施用的发育障碍的模型。我们预计这种独特的模型不仅与 AAT 缺乏疗法的临床前开发高度相关，而且与肺气肿和吸烟研究高度相关。
Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is a genetic disease, α-1 antitrypsin (AAT) deficiency. Humans have only one gene that codes for the AAT protein, but mice have up to six, which made it impossible for decades to create a mouse model of the disease. Here we succeeded in creating this mouse model using CRISPR technology to target all of the mouse genes at once. Importantly, this mouse model spontaneously develops lung disease and recapitulates many aspects of the human disease. We anticipate that this model will be highly relevant not only to the preclinical development of therapeutics for AAT deficiency, but also to emphysema and smoking research. Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a–e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase. With age, Serpina1 null mice develop emphysema spontaneously, which can be induced in younger mice by a lipopolysaccharide challenge. This mouse models not only AAT deficiency but also emphysema and is a relevant genetic model and not one based on developmental impairment of alveolarization or elastase administration. We anticipate that this unique model will be highly relevant not only to the preclinical development of therapeutics for AAT deficiency, but also to emphysema and smoking research.
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DOI：
10.1016/j.ymthe.2017.09.020
发表时间：
2017-11-01
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Borel F;Tang Q;Gernoux G;Greer C;Wang Z;Barzel A;Kay MA;Shultz LD;Greiner DL;Flotte TR;Brehm MA;Mueller C
通讯作者：
Mueller C
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1016/j.ymthe.2017.03.029
发表时间：
2017-06-07
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Mueller C;Gernoux G;Gruntman AM;Borel F;Reeves EP;Calcedo R;Rouhani FN;Yachnis A;Humphries M;Campbell-Thompson M;Messina L;Chulay JD;Trapnell B;Wilson JM;McElvaney NG;Flotte TR
通讯作者：
Flotte TR
影响因子：
15.9
作者：
NAKAMURA, H;YOSHIMURA, K;CRYSTAL, RG
通讯作者：
CRYSTAL, RG
影响因子：
15.9
作者：
Mueller, Christian;Chulay, Jeffrey D.;Flotte, Terence R.
通讯作者：
Flotte, Terence R.