Larger trial justified
A multicenter, international phase 2 trial known as EDELIFE is underway to investigate the safety and efficacy of an in utero treatment for developing males with X-linked hypohidrotic ectodermal dysplasia (XLHED).
This condition is caused by mutations in the gene coding for ectodysplasin A (EDA), a protein that signals the epithelial-mesenchymal transition during embryogenesis. EDA loss or dysfunction precludes binding to its endogenous EDA1 receptor (EDAR), and downstream development of teeth, hair, nails, and skin adnexae, most notably eccrine glands.
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The treatment, ER004, is a first-in-class signaling protein EDA replacement molecule now under investigation by the EspeRare Foundation, with support from the Pierre Fabre Foundation. The pioneering clinical trial is evaluating the delivery of ER004 protein replacement in utero to affected fetuses, allowing antenatal binding to the EDAR. According to the EDELIFE web site, when ER004 is administered to XLHED-affected males in utero, it “should act as a replacement for the missing EDA and trigger the process that leads to the normal development of a baby’s skin, teeth, hair, and sweat glands, leading to better formation of these structures.”
The protein is delivered into the amniotic fluid via a needle and syringe under ultrasound guidance. In a report on this treatment used in a pair of affected twins and a third XLHED-affected male published in 2018, the authors reported that the three babies were able to sweat normally after birth, “and XLHED-related illness had not developed by 14-22 months of age.”
The goal of the prospective, open-label, genotype match–controlled EDELIFE trial is to confirm the efficacy and safety results for ER004 in a larger group of boys, and to determine if it can lead to robust, and long-lasting improvement in XLHED-associated defects.
In the United States, the first pregnant woman to join the study received the treatment in February 2023 at Washington University in St. Louis. Other clinical sites are located in France, Germany, Italy, Spain, and the United Kingdom. Led by principal investigator Holm Schneider, MD, of the University Erlanger-Nurnberg (Germany), researchers are seeking to enroll mothers aged 18 years and older who are genetically confirmed carriers of the XLHED mutation and pregnant with a boy or considering pregnancy. The control group will include XLHED-affected males, 6 months to 60 years old, who are blood relatives of the pregnant woman participating in the study.
Dr. Elaine Siegfried
“This is an unprecedented approach to preventing a significant morbidity affecting boys with XLHED, and a potential model for in utero correction of genetic defects involving embryogenesis,” Elaine Siegfried, MD, professor of pediatrics and dermatology at Saint Louis University, said in an interview. Dr. Siegfried, who has served on the scientific advisory board of the National Foundation for Ectodermal Dysplasias since 1997, added that many years of effort “has finally yielded sufficient funding and identified an international network of experts to support this ambitious trial. We are now seeking participation of the most important collaborators: mothers willing to help establish safety and efficacy of this approach.”
Mary Fete, MSN, RN, executive director of the NFED, said that the EDELIFE clinical trial “provides enormous hope for our families affected by XLHED. It’s extraordinary to think that the baby boys affected by XLHED who have received ER004 are sweating normally and have other improved symptoms. The NFED is proud to have begun and fostered the research for 30-plus years that developed ER004.”
Dr. Siegfried is a member of the independent data monitoring committee for the EDELIFE trial.
Clinicians treating affected families or potentially eligible subjects are encouraged to contact the trial investigators at this link.