Treatment of Polarized Cystic Fibrosis Airway Cells With HGF Prevents VX-661-Rescued F508del-CFTR Destabilization Caused by Prolonged Co-exposure to VX-770.
Treatment of Polarized Cystic Fibrosis Airway Cells With HGF Prevents VX-661-Rescued F508del-CFTR Destabilization Caused by Prolonged Co-exposure to VX-770.
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DOI：
10.3389/fmolb.2021.812101
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发表时间：
2021
影响因子：
5
通讯作者：
Matos P
中科院分区：
文献类型：
--
作者：
Matos AM;Jordan P;Matos P
囊性纤维化是高加索人最常见的遗传性疾病，由CFTR突变引起，其中最常见的是F508del。F508del导致突变的CFTR蛋白的内质网滞留和降解，但也导致通道门控缺陷和质膜半衰期减少。尽管最近在小分子CFTR调节剂药物方面取得了成功，但被批准用于携带F508del-CFTR的CF患者的折叠校正剂/门控增强剂药物组合有时会产生严重的副作用。此前，我们发现，用VX-809+VX-770组合对极化的支气管上皮单层进行长时间、15天的处理会导致上皮去分化效应，我们发现这种效应是由VX-809特异性引起的。此外，VX-770的长期暴露也导致了VX-809拯救的F508del-CFTR的不稳定。值得注意的是，与生理因子HGF共同处理阻止了VX-809介导的上皮分化，并逆转了VX-770对VX-809拯救的CFTR的不稳定作用。在这里，我们表明，VX-661，一种基于VX-809结构开发的第二代校正器，长期治疗不会扰乱极化的支气管上皮单层的上皮完整性。然而，其疗效仍然受到VX-770共同暴露的影响，VX-770是美国和欧洲批准用于治疗F508del-CFTR携带者的所有含有VX-661的联合疗法中存在的增强剂。重要的是，我们发现与HGF共同处理仍然改善了VX-770在VX-661对F508del-CFTR功能挽救中的影响，而没有增加细胞增殖(Ki-67)或改变上皮标志物(ZO-1、E-钙粘素、CK8、CK18)的总体表达。我们的研究结果强调了评估长期接触CFTR调节剂对细胞的影响的重要性，并建议在目前的联合治疗中加入HGF的好处应该得到进一步的研究。
Cystic fibrosis (CF), the most common inherited disease in Caucasians, is caused by mutations in CFTR, the most frequent of which is F508del. F508del causes ER retention and degradation of the mutant CFTR protein, but also defective channel gating and decreased half-life at the plasma membrane. Despite the recent successes with small-molecule CFTR modulator drugs, the folding-corrector/gating-potentiator drug combinations approved for CF individuals carrying F508del-CFTR have sometimes produced severe side effects. Previously, we showed that a prolonged, 15-days treatment of polarized bronchial epithelial monolayers with the VX-809+VX-770 combination resulted in epithelial dedifferentiation effects that we found were caused specifically by VX-809. Moreover, prolonged VX-770 exposure also led to the destabilization of VX-809-rescued F508del-CFTR. Notably, co-treatment with the physiological factor HGF prevented VX-809-mediated epithelial differentiation and reverted the destabilizing effect of VX-770 on VX-809-rescued CFTR. Here, we show that prolonged treatment with VX-661, a second-generation corrector developed based on VX-809 structure, does not perturb epithelial integrity of polarized bronchial epithelial monolayers. Yet, its efficacy is still affected by co-exposure to VX-770, the potentiator present in all VX-661-containing combination therapies approved in the United States and Europe for treatment of F508del-CFTR carriers. Importantly, we found that co-treatment with HGF still ameliorated the impact of VX-770 in F508del-CFTR functional rescue by VX-661, without increasing cell proliferation (Ki-67) or altering the overall expression of epithelial markers (ZO-1, E-cadherin, CK8, CK18). Our findings highlight the importance of evaluating the cellular effects of prolonged exposure to CFTR modulators and suggest that the benefits of adding HGF to current combination therapies should be further investigated.
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影响因子：
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作者：
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DOI：
10.1164/ajrccm.156.6.9611057
发表时间：
1997-12-01
影响因子：
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作者：
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