Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.
Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis.
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DOI：
10.1038/nm.4305
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发表时间：
2017-05
期刊：
影响因子：
82.9
通讯作者：
Garaci E
中科院分区：
文献类型：
--
作者：
Romani L;Oikonomou V;Moretti S;Iannitti RG;D'Adamo MC;Villella VR;Pariano M;Sforna L;Borghi M;Bellet MM;Fallarino F;Pallotta MT;Servillo G;Ferrari E;Puccetti P;Kroemer G;Pessia M;Maiuri L;Goldstein AL;Garaci E
囊性纤维化(CF)是由编码囊性纤维化跨膜传导调节因子(CFTR)的基因突变引起的，这种突变损害了它的氯通道活性。最常见的突变P.Phe508del导致错误折叠的CFTR蛋白的产生，该蛋白具有残留的通道活性，但被过早降解。由于CF发病机制的内在复杂性--包括氯离子通透性受损和持续性肺部炎症--有效的CF治疗需要多种药物的治疗。到目前为止，还没有对CF具有多效性有益作用的个体药物。在这里，我们报道了胸腺肽α1(Tα1)-一种天然存在的多肽，在临床上用作佐剂或免疫治疗剂时具有良好的安全性-纠正CF小鼠以及P.Phe508del突变受试者细胞中的多个组织缺陷的能力。Tα1表现出两种与CFR症状相反的组合特性，即它减少了炎症，增加了CFTR的成熟度、稳定性和活性。通过这种双管齐下的作用，Tα1有很强的潜力成为一种有效的单分子治疗CF的药物。
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride-channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF —which include impaired chloride permeability and persistent lung inflammation—a multidrug approach is required for efficacious CF therapy. To date, no individual, drug with pleiotropic beneficial effects for CF is available. Here we report on the ability of thymosin alpha 1 (Tα1)—a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent—to rectify the multiple tissue defects in CF mice as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology; namely, it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 offers a strong potential to be an efficacious single molecule-based therapeutic agent in CF.