Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis.
Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis.
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DOI：
10.1126/scitranslmed.3008680
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发表时间：
2014-07-23
影响因子：
17.1
通讯作者：
Gentzsch M
中科院分区：
文献类型：
--
作者：
Cholon DM;Quinney NL;Fulcher ML;Esther CR Jr;Das J;Dokholyan NV;Randell SH;Boucher RC;Gentzsch M
囊性纤维化（CF）是由CF跨膜传导调节因子（CFTR）突变引起的。新开发的“校正剂”，如lumacaftor (VX-809)，可改善CFTR的成熟和运输，以及“增强剂”，如ivacaftor (VX-770)，可增强通道活性，可能为CF治疗提供重要进展。尽管VX-770在一小部分仅影响通道活性的突变（G551D）患者中显示出显著的临床疗效，但单一化合物不足以治疗更常见的CFTR突变（ΔF508）患者。因此，ΔF508患者可能需要同时使用矫正剂和增强剂来获得临床益处。然而，尽管这种药物组合在急性治疗中的有效性已在体外得到证实，但慢性治疗的影响尚未确定。在人原代气道上皮细胞的研究中，我们发现用VX-770急性和慢性治疗均能改善G551D突变细胞的CFTR功能，与临床研究一致。相反，在ΔF508纯合子培养中，慢性给药VX-770导致vx -809介导的CFTR校正的剂量依赖性逆转。这一结果反映了VX-770修正后的ΔF508 CFTR的不稳定性，显著提高了其周转率。慢性VX-770治疗也降低了成熟野生型CFTR水平和功能。这些发现表明，长期使用CFTR增强剂和校正剂治疗可能会产生短期研究无法预测的意想不到的效果。联合使用这些药物以最大限度地挽救ΔF508 CFTR可能需要改变剂量和/或开发不干扰CFTR稳定性的新增强剂化合物。
Cystic Fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). Newly developed “correctors” such as lumacaftor (VX-809) that improve CFTR maturation and trafficking and “potentiators” such as ivacaftor (VX-770) that enhance channel activity may provide important advances in CF therapy. Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation (G551D) that affects only channel activity, a single compound is not sufficient to treat patients with the more common CFTR mutation, ΔF508. Thus, patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit. However, whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro, the impact of chronic therapy has not been established. In studies of human primary airway epithelial cells, we found that both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies. In contrast, chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated CFTR correction in ΔF508 homozygous cultures. This result reflected the destabilization of corrected ΔF508 CFTR by VX-770, dramatically increasing its turnover rate. Chronic VX-770 treatment also reduced mature wild-type CFTR levels and function. These findings demonstrate that chronic treatment with CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies. Combining of these drugs to maximize rescue of ΔF508 CFTR may require changes in dosing and/or development of new potentiator compounds that do not interfere with CFTR stability.
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影响因子：
4
作者：
Chang XB;Mengos A;Hou YX;Cui L;Jensen TJ;Aleksandrov A;Riordan JR;Gentzsch M
通讯作者：
Gentzsch M
影响因子：
2
作者：
Esther, Charles R., Jr.;Jasin, H. Matias;Boysen, Gunnar
通讯作者：
Boysen, Gunnar
影响因子：
64.8
作者：
DALEMANS, W;BARBRY, P;LAZDUNSKI, M
通讯作者：
LAZDUNSKI, M
影响因子：
5.6
作者：
Aleksandrov, Andrei A.;Kota, Pradeep;Cui, Liying;Jensen, Tim;Alekseev, Alexey E.;Reyes, Santiago;He, Lihua;Gentzsch, Martina;Aleksandrov, Luba A.;Dokholyan, Nikolay V.;Riordan, John R.
通讯作者：
Riordan, John R.
DOI：
10.1152/ajplung.00016.2009
发表时间：
2010-03-01
影响因子：
4.9
作者：
Cholon, Deborah M.;O'Neal, Wanda K.;Gentzsch, Martina
通讯作者：
Gentzsch, Martina