目前已报道的大部分2,100种CFTR基因变体在囊性纤维化（CF）的疾病易感性和导致CFTR功能障碍的分子和细胞机制方面仍然未知。由于一些罕见的变体可能对目前批准的调节剂有反应，定性他们的缺陷和对这些药物的反应对于有效治疗不适合当前治疗的CF患者至关重要。在这里，我们评估了罕见变体p.Arg334Trp对CFTR通路和功能以及对现有CFTR调节剂的反应的影响。为此，我们对来自10名CFTR基因的一个或两个等位基因带有p.Arg334Trp变体的CF患者的肠道类器官进行了促进假丝酵母素引起的肿胀（FIS）实验。同时，还产生了一种新的p.Arg334Trp-CFTR表达的CFBE细胞系，以单独表征变异体。结果显示，p.Arg334Trp-CFTR不会显著影响CFTR的质量膜通路，并证实了残余CFTR功能。这种CFTR变体由目前可用的CFTR调节剂独立于第二等位基因的变体来挽救。该研究预测，在至少有一个p.Arg334Trp变体的CF患者中，CFTR调节剂将带来临床益处，证明了通过治疗诊断来延长已批准药物的标签，个性化医学的高潜力。我们建议卫生保险制度/国家卫生服务考虑这种个性化方法用于药物报销政策。版权所有©2023 Railean，Rodrigues，Ramalho，Silva，Bartosch，Farinha，Pankonien和Amaral。

Most of the 2,100 CFTR gene variants reported to date are still unknown in terms of their disease liability in Cystic Fibrosis (CF) and their molecular and cellular mechanism that leads to CFTR dysfunction. Since some rare variants may respond to currently approved modulators, characterizing their defect and response to these drugs is essential for effective treatment of people with CF (pwCF) not eligible for the current treatment. Here, we assessed how the rare variant, p.Arg334Trp, impacts on CFTR traffic and function and its response to existing CFTR modulators. To this end, we performed the forskolin-induced swelling (FIS) assay on intestinal organoids from 10 pwCF bearing the p.Arg334Trp variant in one or both alleles of the CFTR gene. In parallel, a novel p.Arg334Trp-CFTR expressing CFBE cell line was generated to characterize the variant individually. Results show that p.Arg334Trp-CFTR does not significantly affect the plasma membrane traffic of CFTR and evidences residual CFTR function. This CFTR variant is rescued by currently available CFTR modulators independently of the variant in the second allele. The study, predicting clinical benefit for CFTR modulators in pwCF with at least one p.Arg334Trp variant, demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs for pwCF carrying rare CFTR variants. We recommend that this personalized approach should be considered for drug reimbursement policies by health insurance systems/national health services.Copyright © 2023 Railean, Rodrigues, Ramalho, Silva, Bartosch, Farinha, Pankonien and Amaral.