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

IF 5.4 2区 医学 Q1 RESPIRATORY SYSTEM
Anne-Sophie Bonnel, Tiphaine Bihouée, Mélanie Ribault, Marine Driessen, David Grèvent, Frantz Foissac, Ngoc Hoa Truong, Myriam Benhamida, Baptiste Arnouat, Roxana Borghese, Frédérique Chedevergne, Laure Couderc-Kohen, Jennifer da Silva, Dominique Grenet, Véronique Houdouin, Anais Le, Sarah Marchal, Eric Deneuville, Delphine Pouradier, Véronique Rousseau, Jean-Marc Treluyer, Arnaud Francart, Julie Steffann, Philippe Reix, Sihem Benaboud, Marie France Mamzer, Yves Ville, Clémence Martin, Pierre-Régis Burgel, Isabelle Sermet-Gaudelus
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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.

首个使用CFTR调节剂治疗囊性纤维化胎儿的实际研究:来自module - cf研究的报告。
背景:我们旨在建立一个在子宫内用变异特异性治疗(VST)治疗母囊性纤维化(CF)胎儿双胎的队列,以评估治疗胎粪肠梗阻(MI)的疗效和潜在的不良反应。方法:如果胎儿有CF的遗传诊断,并且携带至少一种对VST应答的变异,则包括双胎。标准化评估包括VST前磁共振成像(MRI)、重复超声(US)和脐带血、母婴血浆中VST药物浓度。结果:我们招募了13对夫妇。其中一人退出了研究。VST治疗(Elexacaftor (ELX)/Tezacaftor (TEZ)/ ivvacaftor (IVA) (ETI) n = 11, ivvacaftor (IVA) n = 1)给予妊娠19至36周的孕妇,中位[IQR]为35[55]天,作为MI的治疗指征(n = 8)或作为胎儿cf相关肠道症状的第三级预防(n = 4)。一个胎儿在引入ETI后肠扩张增加。MRI显示肠闭锁。一组只注射了两剂。另外6例在ETI后14bb0天内观察到MI的消退。胎儿发育和新生儿耐受性良好。即使在ETI母乳喂养的婴儿中,出生时的粪便弹性酶也始终低于200 ng/g。脐带与母体浓度的中位比值为ELX 0.40, IVA 0.54, TEZ 1.59。结论:从妊娠晚期开始使用ETI可使心肌梗死得到缓解。经胎盘移植率高。在ETI开始时,胎儿耐受性需要通过标准化评估来监测。
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来源期刊
Journal of Cystic Fibrosis
Journal of Cystic Fibrosis 医学-呼吸系统
CiteScore
10.10
自引率
13.50%
发文量
1361
审稿时长
50 days
期刊介绍: The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.
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