PRenatal mOdulator treatment to PrEvent CF complicaTions (PROTECT) workshop report

Sylvia Szentpetery¹, Dara Riva², Yair J Blumenfeld³, John F Engelhardt⁴, Carmen Luna-Paredes⁵, Carlos Milla⁶, Elena K Schneider-Futschik⁷, Jeanne S Sheffield⁸, Rebecca Darrah⁹, Jane C Davies¹⁰, Patrick A Flume¹¹, Kimberly E Foil¹², Christopher N Fortner¹³, Jennifer S Guimbellot¹⁴, Anne D Lyerly¹⁵, Nicole Mayer-Hamblett¹⁶, Clement L Ren¹⁷, Jacquelyn Spano⁶, Emma M Tillman¹⁸, Aaron Trimble¹⁹, Benjamin S Wilfond²⁰, Jennifer L Taylor-Cousar²¹

Affiliations

¹ Medical University of South Carolina, Department of Pediatrics, Charleston, SC, USA.
² Cystic Fibrosis Foundation, Bethesda, MD, USA.
³ Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Anatomy and Cell Biology, University of Iowa, Carver College of Medicine, Iowa City, IA, USA.
⁵ Multidisciplinary Cystic Fibrosis Unit. Department of Paediatrics. Hospital Universitario 12 de Octubre, Madrid, Spain.
⁶ Center for Excellence in Pulmonary Biology, Stanford University, Palo Alto, CA USA.
⁷ Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
⁸ Department of Obstetrics and Gynecology, Johns Hopkins University, Baltimore, MD, USA.
⁹ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
¹⁰ National Heart & Lung Institute, Imperial College London and Royal Brompton Hospital, Guy's & St Thomas' Trust, London, UK.
¹¹ Medical University of South Carolina, Department of Pediatrics, Charleston, SC, USA; Medical University of South Carolina, Department of Medicine, Charleston, SC, USA.
¹² Medical University of South Carolina, Department of Medicine, Charleston, SC, USA.
¹³ SUNY Upstate Medical University, Syracuse, NY, USA.
¹⁴ ACRI: Arkansas Children's Research Institute/University of Arkansas for Medical Sciences, Little Rock, AR, USA.
¹⁵ Department of Social Medicine and Center for Bioethics, University of North Carolina at Chapel Hill, USA.
¹⁶ Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁷ Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁸ Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁹ Division of Pulmonary, Allergy, and Critical Care Medicine, Oregon Health & Science University, Portland, OR, USA.
²⁰ Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
²¹ National Jewish Health, Departments of Internal Medicine and Pediatrics, Denver, CO, USA. Electronic address: taylorcousarj@njhealth.org.

PMID: 40754574
DOI: 10.1016/j.jcf.2025.07.015

Review

PRenatal mOdulator treatment to PrEvent CF complicaTions (PROTECT) workshop report

Sylvia Szentpetery et al. J Cyst Fibros. 2025.

. 2025 Aug 2:S1569-1993(25)01538-3.

doi: 10.1016/j.jcf.2025.07.015. Online ahead of print.

Authors

Affiliations

¹ Medical University of South Carolina, Department of Pediatrics, Charleston, SC, USA.
² Cystic Fibrosis Foundation, Bethesda, MD, USA.
³ Department of Obstetrics & Gynecology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Anatomy and Cell Biology, University of Iowa, Carver College of Medicine, Iowa City, IA, USA.
⁵ Multidisciplinary Cystic Fibrosis Unit. Department of Paediatrics. Hospital Universitario 12 de Octubre, Madrid, Spain.
⁶ Center for Excellence in Pulmonary Biology, Stanford University, Palo Alto, CA USA.
⁷ Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia.
⁸ Department of Obstetrics and Gynecology, Johns Hopkins University, Baltimore, MD, USA.
⁹ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
¹⁰ National Heart & Lung Institute, Imperial College London and Royal Brompton Hospital, Guy's & St Thomas' Trust, London, UK.
¹¹ Medical University of South Carolina, Department of Pediatrics, Charleston, SC, USA; Medical University of South Carolina, Department of Medicine, Charleston, SC, USA.
¹² Medical University of South Carolina, Department of Medicine, Charleston, SC, USA.
¹³ SUNY Upstate Medical University, Syracuse, NY, USA.
¹⁴ ACRI: Arkansas Children's Research Institute/University of Arkansas for Medical Sciences, Little Rock, AR, USA.
¹⁵ Department of Social Medicine and Center for Bioethics, University of North Carolina at Chapel Hill, USA.
¹⁶ Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁷ Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁸ Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁹ Division of Pulmonary, Allergy, and Critical Care Medicine, Oregon Health & Science University, Portland, OR, USA.
²⁰ Seattle Children's Research Institute, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
²¹ National Jewish Health, Departments of Internal Medicine and Pediatrics, Denver, CO, USA. Electronic address: taylorcousarj@njhealth.org.

PMID: 40754574
DOI: 10.1016/j.jcf.2025.07.015

Abstract

Background: Data from cystic fibrosis (CF) animal models and case studies suggests that in utero administration of CF transmembrane conductance regulator (CFTR) modulators (variant specific therapies, VST) can rescue CFTR-related pathophysiology in the fetus. Use of VST during pregnancy to prevent disease in infants has not been systematically studied. Through stakeholder engagement, we sought to determine if formal research evaluation is warranted.

Methods: We surveyed CF care center directors to assess their awareness of the potential off-label use of VST for in utero treatment of a fetus with CF. We then conducted a one-day, international multidisciplinary workshop to review available pre-clinical and clinical data, embryology principles and federal drug regulation considerations, identify knowledge gaps, and consider future clinical study designs.

Results: Sixty-two unique individuals responded to the survey; 92% were aware of use of VST to treat pregnant females who are CF carriers for the prevention of CF complications in the fetus. Expert workshop presentations suggested that use of VST in pregnant females carrying a fetus with CF to mitigate complications of CF is relatively safe and effective in animal models and human case series to date. Further research is needed to understand the optimal timing of VST initiation during pregnancy to improve clinical outcomes, to understand VST pharmacokinetics, and optimize dosing of VST during pregnancy and lactation, and to evaluate the long-term infant safety among those exposed to VST in utero.

Conclusions: Based on available data and knowledge gaps, stakeholders agreed that formal evaluation of in utero and early life VST therapy in a prospective trial is warranted.

Keywords: CFTR modulator; Meconium ileus; Prenatal; Variant specific therapy; Vas deferens.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest In the last 36 months, JTC has received grants to her institution from the Cystic Fibrosis Foundation, the National Institutes of Health, Vertex Pharmaceuticals Incorporated, Eloxx, 4DMT, Splisense and Recode; she has received fees from Vertex Pharmaceuticals Incorporated related to consultation on clinical research design; and has also served on advisory boards and/or provided clinical trial design consultation for 4DMT and Kither Biotech. JTC served on a DMC for AbbVie. JTC serves as the adult patient care representative to the CFF Board of Trustees, and on the CF Foundation’s Clinical Research Executive Committee, Clinical Research Advisory Board, as immediate past chair of the CF TDN’s Sexual Health, Reproduction and Gender Research Working Group, and as Co-Chair of the Heath Equity Team Science Awards study section. She also serves on the scientific advisory board for Emily’s Entourage, and as the Chair-Elect of the American Thoracic Society International Conference Committee. She is an Associate Editor for the Journal of Cystic Fibrosis and a member of the International Advisory Board for the Lancet Respiratory Medicine Journal. JTC serves on the Clinical Trials Review (CTLR) Study section for the National Institutes of Health/National Heart. Blood, Lung Institute. AT has received grants to his institution from the Cystic Fibrosis Foundation, Vertex Pharmaceuticals Incorporated, and Recode, NMH reports grants from CFF and NIH. CLP (Carmen Luna-Paredes has received fees from Vertex Pharmaceuticals Incorporated related to participation in advisory boards and as a speaker in symposiums and scientific meetings. CM has received research grants to his institution from the US National Institutes of Health, US Cystic Fibrosis Foundation and US Cystic Fibrosis Research Institute; support to his institution for clinical trials from Vertex Pharmaceuticals, ReCode Inc., Respirion Inc., Clarametyx Inc., and Genentech; and honoraria from Vertex Pharmaceuticals for educational materials development and presentation. KF declares no conflict of interest. JCD has received grants from the UK Cystic Fibrosis Trust, Cystic Fibrosis Foundation, Cystic Fibrosis Ireland, NIHR and Life Arc. She receives royalties from Boehringer-Ingelheim via her employing institution. She has received consulting fees from Vertex Pharmaceuticals, Boehringer-Ingelheim, Arcturus, Enterprise Therapeutics, Recode, LifeArc, Genentech, Tavanta, and Kither Biotech. She has received honoraria for presentations from Vertex Pharmaceuticals Ltd, Boehringer-Ingelheim and LifeArc. She served as the Deputy Editor for the Journal of Cystic Fibrosis and the current President of the European Cystic Fibrosis Society. SES has received grants to her institution from the Cystic Fibrosis Foundation, Vertex Pharmaceuticals Incorporated, served as an investigator on AbbVie, Sound Pharmaceuticals, Vertex, and Calithera Biosciences studies. JSG has received grants to her institution from the Cystic Fibrosis Foundation and the National Institutes of Health and received one-time fees for participation in an advisory board in 2023 from Vertex Pharmaceuticals.

Publication types

Actions

LinkOut - more resources

Full Text Sources
- ClinicalKey

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

PRenatal mOdulator treatment to PrEvent CF complicaTions (PROTECT) workshop report

Affiliations

PRenatal mOdulator treatment to PrEvent CF complicaTions (PROTECT) workshop report

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

LinkOut - more resources

Full Text Sources