Tümmler Burkhard, Pallenberg Sophia Theres, Dittrich Anna-Maria, Graeber Simon Y, Naehrlich Lutz, Sommerburg Olaf, Mall Marcus A
Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
German Center for Lung Research, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Hannover Medical School, Hannover, Germany.
Mol Cell Pediatr. 2025 May 5;12(1):6. doi: 10.1186/s40348-025-00194-0.
Cystic fibrosis (CF) is a systemic disorder of exocrine glands that is caused by mutations in the CFTR gene.
The basic defect in people with CF (pwCF) leads to impaired epithelial transport of chloride and bicarbonate that can be assessed by CFTR biomarkers, i.e. the β-adrenergic sweat rate and sweat chloride concentration (SCC), chloride conductance of the nasal respiratory epithelium (NPD), urine secretion of bicarbonate, intestinal current measurements (ICM) of chloride secretory responses in rectal biopsies and in bioassays of chloride transport in organoids or cell cultures. CFTR modulators are a novel class of drugs that improve defective posttranslational processing, trafficking and function of mutant CFTR. By April 2025, triple combination therapy with the CFTR potentiator ivacaftor (IVA) and the CFTR correctors elexacaftor (ELX) and tezacaftor (TEZ) has been approved in Europe for the treatment of all pwCF who do not carry two minimal function CFTR mutations. Previous phase 3 and post-approval phase 4 studies in pwCF who harbour one or two alleles of the major mutation F508del consistently reported significant improvements of lung function and anthropometry upon initiation of ELX/TEZ/IVA compared to baseline. Normalization of SCC, NPD and ICM correlated with clinical outcomes on the population level, but the restoration of CFTR function was diverse and not predictive for clinical outcome in the individual patient. Theratyping of non-F508del CF genotypes in patient-derived organoids and cell cultures revealed for most cases clinically meaningful increases of CFTR activity upon exposure to ELX/TEZ/IVA. Likewise, every second CF patient with non-F508del genotypes improved in SCC and clinical outcome upon exposure to ELX/TEZ/IVA indicating that triple CFTR modulator therapy is potentially beneficial for all pwCF who do not carry two minimal function CFTR mutations. This group who is not eligible for CFTR modulators may opt for gene addition therapy in the future, as the first-in-human trial with a recombinant lentiviral vector is underway.
The upcoming generation of pwCF will probably experience a rather normal life in childhood and adolescence. To classify the upcoming personal signatures of CF disease in the times of efficient modulators, we need more sensitive CFTR biomarkers that address the long-term course of airway and gut microbiome, host defense, epithelial homeostasis and multiorgan metabolism.
囊性纤维化（CF）是一种外分泌腺的全身性疾病，由CFTR基因突变引起。
CF患者（pwCF）的基本缺陷导致氯离子和碳酸氢根离子的上皮转运受损，这可以通过CFTR生物标志物进行评估，即β-肾上腺素能汗液分泌率和汗液氯离子浓度（SCC）、鼻呼吸上皮的氯离子传导率（NPD）、尿液中碳酸氢根的分泌、直肠活检中氯离子分泌反应的肠道电流测量（ICM）以及类器官或细胞培养中氯离子转运的生物测定。CFTR调节剂是一类新型药物，可改善突变型CFTR缺陷的翻译后加工、转运和功能。截至2025年4月，CFTR增强剂依伐卡托（IVA）与CFTR校正剂艾列卡托（ELX）和替扎卡托（TEZ）的三联联合疗法已在欧洲获批，用于治疗所有未携带两个最小功能CFTR突变的pwCF。之前在携带一个或两个主要突变F508del等位基因的pwCF患者中进行的3期研究和批准后4期研究一致报告，与基线相比，开始使用ELX/TEZ/IVA后肺功能和人体测量指标有显著改善。SCC、NPD和ICM的正常化在人群水平上与临床结果相关，但CFTR功能的恢复各不相同，对个体患者的临床结果没有预测性。在患者来源的类器官和细胞培养中对非F508del CF基因型进行治疗分型显示，在大多数情况下，暴露于ELX/TEZ/IVA后CFTR活性有临床上有意义的增加。同样，每两名具有非F508del基因型的CF患者在暴露于ELX/TEZ/IVA后SCC和临床结果都有所改善，这表明三联CFTR调节剂疗法可能对所有未携带两个最小功能CFTR突变的pwCF有益。这一不符合CFTR调节剂治疗条件的群体未来可能会选择基因添加疗法，因为一项使用重组慢病毒载体的人体首次试验正在进行中。
即将到来的一代pwCF患者在童年和青少年时期可能会过上相当正常的生活。为了在有效调节剂时代对即将出现的CF疾病个人特征进行分类，我们需要更敏感的CFTR生物标志物，以解决气道和肠道微生物群、宿主防御、上皮内稳态和多器官代谢的长期过程。
