Silva Iris A L, Railean Violeta, Duarte Aires, Amaral Margarida D
BioISI-Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, 1749-016 Lisboa, Portugal.
J Pers Med. 2021 May 16;11(5):421. doi: 10.3390/jpm11050421.
As highly effective CFTR modulator therapies (HEMT) emerge, there is an unmet need to find effective drugs for people with CF (PwCF) with ultra-rare mutations who are too few for classical clinical trials and for whom there are no drug discovery programs. Therefore, biomarkers reliably predicting the benefit from CFTR modulator therapies are essential to find effective drugs for PwCF through personalized approaches termed theranostics. Here, we assess CFTR basal function and the individual responses to CFTR modulators in primary human nasal epithelial (pHNE) cells from PwCF carrying rare mutations and compare these measurements with those in native rectal biopsies and intestinal organoids, respectively, in the same individual. The basal function in pHNEs shows good correlation with CFTR basal function in rectal biopsies. In parallel, CFTR rescue in pHNEs by CFTR modulators correlates to that in intestinal organoids. Altogether, results show that pHNEs are a bona fide theranostic model to assess CFTR rescue by CFTR modulator drugs, in particular for PwCF and rare mutations.
随着高效CFTR调节剂疗法（HEMT）的出现，对于患有超罕见突变的囊性纤维化患者（PwCF）来说，存在着未满足的需求，即找到有效的药物。这些患者数量太少，无法进行经典的临床试验，而且也没有药物研发项目。因此，可靠地预测CFTR调节剂疗法益处的生物标志物对于通过称为治疗诊断学的个性化方法为PwCF找到有效药物至关重要。在这里，我们评估了携带罕见突变的PwCF的原代人鼻上皮（pHNE）细胞中CFTR的基础功能以及对CFTR调节剂的个体反应，并分别将这些测量结果与同一个体的天然直肠活检组织和肠道类器官中的测量结果进行比较。pHNE中的基础功能与直肠活检组织中CFTR的基础功能显示出良好的相关性。同时，CFTR调节剂在pHNE中对CFTR的挽救作用与肠道类器官中的情况相关。总之，结果表明pHNE是评估CFTR调节剂药物对CFTR挽救作用的真正治疗诊断模型，特别是对于PwCF和罕见突变。
