Engineered mutant α-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis-based cell and mice models.
Engineered mutant α-ENaC subunit mRNA delivered by lipid nanoparticles reduces amiloride currents in cystic fibrosis-based cell and mice models.
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DOI：
10.1126/sciadv.abc5911
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发表时间：
2020-11
期刊：
影响因子：
13.6
通讯作者：
Sahay G
中科院分区：
文献类型：
--
作者：
Mukherjee A;MacDonald KD;Kim J;Henderson MI;Eygeris Y;Sahay G
用于治疗囊性纤维化的纳米颗粒递送的ENaC抑制性mRNA。囊性纤维化（CF）是由氯离子传导CF跨膜传导调节因子（CFTR）基因突变引起的。CF中的气道脱水和粘膜纤毛清除受损被认为导致紧张性上皮钠通道（ENaC）活性，其驱动阿米洛利敏感的产电钠吸收。通过抑制ENaC减少钠吸收可以逆转气道表面液体脱水。在这里，我们通过引入失活突变体ENaC α mRNA（αmutENaC）来抑制内源性异源三聚体ENaC通道。脂质纳米粒携带αmutENaC转染在CF为基础的气道细胞在体外和体内。我们观察到宏观以及阿米洛利敏感的ENaC电流和CF气道细胞的气道表面液体高度的增加显着减少。同样，鼻内转染αmutENaC mRNA降低了CFTRKO小鼠对阿米洛利敏感的鼻电位差。这些数据表明，基于mRNA的ENaC抑制是减少粘液脱水的有力策略，并且具有治疗所有患者的CF的治疗潜力，与基因型无关。
A nanoparticle delivered ENaC-inhibitory mRNA for the treatment of cystic fibrosis. Cystic fibrosis (CF) results from mutations in the chloride-conducting CF transmembrane conductance regulator (CFTR) gene. Airway dehydration and impaired mucociliary clearance in CF is proposed to result in tonic epithelial sodium channel (ENaC) activity, which drives amiloride-sensitive electrogenic sodium absorption. Decreasing sodium absorption by inhibiting ENaC can reverse airway surface liquid dehydration. Here, we inhibit endogenous heterotrimeric ENaC channels by introducing inactivating mutant ENaC α mRNA (αmutENaC). Lipid nanoparticles carrying αmutENaC were transfected in CF-based airway cells in vitro and in vivo. We observed a significant decrease in macroscopic as well as amiloride-sensitive ENaC currents and an increase in airway surface liquid height in CF airway cells. Similarly, intranasal transfection of αmutENaC mRNA decreased amiloride-sensitive nasal potential difference in CFTRKO mice. These data suggest that mRNA-based ENaC inhibition is a powerful strategy for reducing mucus dehydration and has therapeutic potential for treating CF in all patients, independent of genotype.
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影响因子：
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