Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany.
German Centre for Lung Research (DZL), Associated Partner Site, 13353 Berlin, Germany.
Int J Mol Sci. 2023 Aug 2;24(15):12365. doi: 10.3390/ijms241512365.
CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare mutations responsive in Fischer rat thyroid cells, including , but not . However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a homozygous patient and an homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in / and / pHNECs. In the / and the / patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare mutations.
CFTR 调节剂疗法联合 elexacaftor/tezacaftor/ivacaftor（ETI）已在欧洲获批用于至少携带一个 F508del 等位基因的 CF 患者。在美国，ETI 的适应证已扩展至 177 种对 Fischer 大鼠甲状腺细胞有反应的罕见突变，包括但不限于 G85E 或 N1303K。然而，关于 ETI 对 G85E 或 N1303K CFTR 功能的影响的知识仍然有限。本研究在纯合子患者和杂合子患者的原代人鼻上皮细胞（pHNEC）中测量了 ETI 的体外作用。通过使用临床终点（包括多次呼吸冲洗和肺 MRI）和 CFTR 生物标志物汗液氯化物浓度（SCC）、鼻电位差（NPD）和肠道电流测量（ICM），在开始 ETI 前后评估了这些患者体内 ETI 治疗的效果。ETI 增加了 / 和 / pHNEC 中 CFTR 介导的氯离子转运。在 / 和 / 患者中，我们观察到在开始 ETI 后，肺功能、SCC 和呼吸道及直肠上皮 CFTR 功能得到改善。这种将临床前体外测试与随后的体内验证相结合的方法可以促进 CFTR 调节剂治疗的应用，并为携带罕见突变的患者提供精准医疗。
