囊性纤维化中使用CFTR调节剂进行胎儿治疗的首个真实世界研究：MODUL-CF研究报告

First real-world study of fetal therapy with CFTR modulators in cystic fibrosis: Report from the MODUL-CF study.

作者信息

Bonnel Anne-Sophie, Bihouée Tiphaine, Ribault Mélanie, Driessen Marine, Grèvent David, Foissac Frantz, Truong Ngoc Hoa, Benhamida Myriam, Arnouat Baptiste, Borghese Roxana, Chedevergne Frédérique, Couderc-Kohen Laure, da Silva Jennifer, Grenet Dominique, Houdouin Véronique, Le Anais, Marchal Sarah, Deneuville Eric, Pouradier Delphine, Rousseau Véronique, Treluyer Jean-Marc, Francart Arnaud, Steffann Julie, Reix Philippe, Benaboud Sihem, Mamzer Marie France, Ville Yves, Martin Clémence, Burgel Pierre-Régis, Sermet-Gaudelus Isabelle

机构信息

Centre de Référence Maladies rares, Mucoviscidose et maladies apparentées. Hôpital Necker Enfants Malades. Assistance Publique Hôpitaux de Paris. Paris. France; Cystic Fibrosis Center. Hôpital Mignot. Le Chesnay. France.

Cystic Fibrosis Center. Centre Hospitalier Universitaire. Nantes, France.

出版信息

J Cyst Fibros. 2025 May;24(3):457-465. doi: 10.1016/j.jcf.2025.03.009. Epub 2025 Mar 24.

DOI:10.1016/j.jcf.2025.03.009

PMID:40133101

Abstract

BACKGROUND

We aimed to build a cohort of Maternal-Cystic Fibrosis (CF) fetal dyads treated in utero with Variant Specific Therapy (VST), to assess the efficacy on Meconium Ileus (MI) and potential adverse effects of treatment.

METHODS

Dyads were included if the foetus had a genetic diagnosis of CF and carried at least one variant responsive to VST. Standardized assessment included pre-VST Magnetic Resonance Imaging (MRI), repeated ultrasound (US), and VST drug concentrations in cord blood, maternal and infant plasma.

RESULTS

We enrolled 13 dyads. One withdrew from the study. VST therapies (Elexacaftor (ELX)/Tezacaftor (TEZ)/Ivacaftor(IVA) (ETI) n = 11, ivacaftor (IVA) n = 1) were administered to the pregnant women between 19 and 36 weeks' of gestation for a median[IQR] of 35[55] days, either as a curative indication of MI (n = 8) or as a tertiary prevention of fetal CF-related intestinal symptoms (n = 4). One foetus experienced increased bowel dilatation after ETI introduction. MRI revealed intestinal atresia. One dyad received only 2 doses. In the other 6 cases, resolution of MI was observed within 14[10] days of ETI. Fetal development and neonatal tolerance were excellent. Fecal elastase at birth was always below 200 ng/g even in the ETI breast-fed infant. Cord-to-maternal concentration yielded median ratios of 0.40 for ELX, 0.54 for IVA and 1.59 for TEZ.

CONCLUSION

ETI administration from the third trimester of pregnancy enables MI resolution. Trans-placental transfer is high. Fetal tolerance at ETI initiation needs to be monitored by a standardized assessment.

摘要

背景

我们旨在建立一个接受子宫内变异特异性疗法（VST）治疗的母胎-囊性纤维化（CF）二元队列，以评估其对胎粪性肠梗阻（MI）的疗效及治疗的潜在不良反应。

方法

如果胎儿有CF的基因诊断且携带至少一种对VST有反应的变异，则纳入二元队列。标准化评估包括VST前的磁共振成像（MRI）、重复超声检查（US）以及脐血、母体和婴儿血浆中的VST药物浓度。

结果

我们纳入了13个二元队列。其中1个退出研究。在妊娠19至36周期间，对孕妇给予VST治疗（依列卡福托（ELX）/替扎卡福托（TEZ）/依伐卡托（IVA）（ETI），n = 11；依伐卡托（IVA），n = 1），中位[四分位间距]治疗时间为35[55]天，治疗指征为MI的根治（n = 8）或作为胎儿CF相关肠道症状的三级预防（n = 4）。1例胎儿在引入ETI后肠扩张增加。MRI显示肠道闭锁。1个二元队列仅接受了2剂治疗。在其他6例中，在ETI治疗后的14[10]天内观察到MI缓解。胎儿发育和新生儿耐受性良好。即使是接受ETI治疗并母乳喂养的婴儿，出生时粪便弹性蛋白酶水平也始终低于200 ng/g。脐血与母体浓度的中位比值，ELX为0.40，IVA为0.54，TEZ为1.59。