A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants.
A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants.
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DOI：
10.3390/jpm11070643
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发表时间：
2021-07-07
影响因子：
--
通讯作者：
Lukacs GL
中科院分区：
文献类型：
--
作者：
Veit G;Velkov T;Xu H;Vadeboncoeur N;Bilodeau L;Matouk E;Lukacs GL
Trikafta是一种三联药物，由折叠校正剂VX-661（tezacaftor），VX-445（elexacaftor）和门控增效剂VX-770（ivacaftor）组成，为患有最常见的囊性纤维化（CF）突变F508 del的患者提供了前所未有的临床益处。Trikafta适应症最近扩展到CF跨膜传导调节因子（CFTR）中的另外177个突变。为了尽可能减少药物给药的终身药理学和经济负担，如果可能的话，我们确定了必要和足够的调节剂组合，其可以在临床前环境中为选定的突变体实现最大益处。为此，分别在支气管上皮细胞系和患者来源的人原代鼻上皮细胞（HNE）中研究了单个校正子响应性罕见突变体的生化和功能拯救。VX-445使VX-661或其他I型校正剂校正的P67 L-、L206 W-或S549 R-CFTR的质膜密度适度增加。然而，HNE的短路电流测量发现，VX-661 + VX-770对S549 R-CFTR以及VX-661 + VX-445组合对P67 L-和L206 W-CFTR实现了与Trikafta相当的校正。因此，引入第三种调节剂可能不会为具有罕见CFTR错义突变子集的患者提供额外的益处。这些结果还强调，HNE作为一种精确的医学模型，能够优化突变特异性调节剂组合，以最大限度地提高其疗效，并最大限度地减少CF患者的终身药物暴露。
Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.
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DOI：
10.1016/j.jbc.2021.100595
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Choi M;Park S;Yi JK;Kwon W;Jang S;Kim SY;Yu W;Kim MO;Ryoo ZY;Choi SK
通讯作者：
Choi SK
影响因子：
168.9
作者：
Heijerman, Harry G. M.;McKone, Edward F.;Mccoy, Karen S.
通讯作者：
Mccoy, Karen S.
影响因子：
64.8
作者：
DALEMANS, W;BARBRY, P;LAZDUNSKI, M
通讯作者：
LAZDUNSKI, M
DOI：
10.1038/nrg3849
发表时间：
2015-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
--
作者：
Farinha, Carlos M.;King-Underwood, John;Amaral, Margarida D.
通讯作者：
Amaral, Margarida D.