{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:25:58Z","timestamp":1790796358951,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T00:00:00Z","timestamp":1672963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"German Federal Ministry for Education and Research (BMBF)","doi-asserted-by":"publisher","award":["01KG2008"],"award-info":[{"award-number":["01KG2008"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EspeRare Foundation","award":["01KG2008"],"award-info":[{"award-number":["01KG2008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA\/NF\u03baB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls.<\/jats:p>","DOI":"10.3390\/genes14010153","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T01:48:19Z","timestamp":1672969699000},"page":"153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia"],"prefix":"10.3390","volume":"14","author":[{"given":"Holm","family":"Schneider","sequence":"first","affiliation":[{"name":"Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smail","family":"Hadj-Rabia","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Reference Centre for Genodermatoses and Rare Skin Diseases (MAGEC), Hopital Universitaire Necker-Enfants Malades, Assistance Publique\u2014Hospitals of Paris, University of Paris-Cit\u00e9, 75743 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Faschingbauer","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Hospital Erlangen, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Bodemer","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Reference Centre for Genodermatoses and Rare Skin Diseases (MAGEC), Hopital Universitaire Necker-Enfants Malades, Assistance Publique\u2014Hospitals of Paris, University of Paris-Cit\u00e9, 75743 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothy K.","family":"Grange","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Norton","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Cavalli","sequence":"additional","affiliation":[{"name":"Pediatric Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Tadini","sequence":"additional","affiliation":[{"name":"Pediatric Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Stepan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, University Hospital Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1200-9286","authenticated-orcid":false,"given":"Angus","family":"Clarke","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF10 3AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Encarna","family":"Guill\u00e9n-Navarro","sequence":"additional","affiliation":[{"name":"Medical Genetics Section, Department of Pediatrics, Virgen de la Arrixaca University Hospital, IMIB-Arrixaca, University of Murcia, and CIBERER, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrun","family":"Maier-Wohlfart","sequence":"additional","affiliation":[{"name":"Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6345-4662","authenticated-orcid":false,"given":"Athmane","family":"Bouroubi","sequence":"additional","affiliation":[{"name":"Pierre Fabre M\u00e9dicament, 31100 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6932-5784","authenticated-orcid":false,"given":"Florence","family":"Porte","sequence":"additional","affiliation":[{"name":"EspeRare Foundation, 1202 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.ejmg.2013.01.012","article-title":"The prevalence of X-linked hypohidrotic ectodermal dysplasia (XLHED) in Denmark, 1995-2010","volume":"56","author":"Skovbo","year":"2013","journal-title":"Eur. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13023-021-01735-2","article-title":"No evidence for preferential X-chromosome inactivation as the main cause of divergent phenotypes in sisters with X-linked hypohidrotic ectodermal dysplasia","volume":"16","author":"Schneider","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1000744","DOI":"10.3389\/fgene.2022.1000744","article-title":"Ectodermal dysplasias: New perspectives on the treatment of so far immedicable genetic disorders","volume":"13","author":"Schneider","year":"2022","journal-title":"Front. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.earlhumdev.2010.04.008","article-title":"Prevalence and prevention of severe complications of hypohidrotic ectodermal dysplasia in infancy","volume":"86","author":"Schneider","year":"2010","journal-title":"Early Hum. Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1007\/s00431-013-1985-8","article-title":"Early respiratory and ocular involvement in X-linked hypohidrotic ectodermal dysplasia","volume":"172","author":"Dietz","year":"2013","journal-title":"Eur. J. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1002\/ajmg.a.38343","article-title":"Automatic recognition of the XLHED phenotype from facial images","volume":"173","author":"Schneider","year":"2017","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1093\/hmg\/10.9.953","article-title":"Ectodysplasin is released by proteolytic shedding and binds to the EDAR protein","volume":"10","author":"Elomaa","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/414913a","article-title":"Gene defect in ectodermal dysplasia implicates a death domain adapter in development","volume":"414","author":"Headon","year":"2001","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2668","DOI":"10.1074\/jbc.M008356200","article-title":"The ectodermal dysplasia receptor activates the nuclear factor-kappaB, JNK, and cell death pathways and binds to ectodysplasin A","volume":"276","author":"Kumar","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1136\/jmg.2010.084012","article-title":"Sweating ability and genotype in individuals with X-linked hypohidrotic ectodermal dysplasia","volume":"48","author":"Schneider","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1002\/ajmg.a.36541","article-title":"Genotype-phenotype correlation in boys with X-linked hypohidrotic ectodermal dysplasia","volume":"164","author":"Burger","year":"2014","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1002\/ajmg.a.36436","article-title":"X-linked hypohidrotic ectodermal dysplasia (XLHED): Clinical and diagnostic insights from an international patient registry","volume":"164","author":"Fete","year":"2014","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1055\/s-0043-100106","article-title":"Hypohidrotic ectodermal dysplasia: Breastfeeding complications due to impaired breast development","volume":"77","author":"Faschingbauer","year":"2017","journal-title":"Geburtsh. Frauenheilk."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13069","DOI":"10.1073\/pnas.94.24.13069","article-title":"The Tabby phenotype is caused by mutation in a mouse homologue of the EDA gene that reveals novel mouse and human exons and encodes a protein (ectodysplasin-A) with collagenous domains","volume":"94","author":"Srivastava","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0968-0004(01)01995-8","article-title":"The molecular architecture of the TNF superfamily","volume":"27","author":"Bodmer","year":"2002","journal-title":"Trends Biochem. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1056\/NEJMoa1714322","article-title":"Prenatal correction of X-linked hypohidrotic ectodermal dysplasia","volume":"378","author":"Schneider","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/nm861","article-title":"Permanent correction of an inherited ectodermal dysplasia with recombinant EDA","volume":"9","author":"Gaide","year":"2003","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1086\/521988","article-title":"Significant correction of disease after postnatal administration of recombinant ectodysplasin A in canine X-linked ectodermal dysplasia","volume":"81","author":"Casal","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1002\/ajmg.a.32916","article-title":"Neonatal treatment with recombinant ectodysplasin prevents respiratory disease in dogs with X-linked ectodermal dysplasia","volume":"149","author":"Mauldin","year":"2009","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1038\/jid.2014.264","article-title":"Prenatal therapy in developmental disorders: Drug targeting via intra-amniotic injection to treat X-linked hypohidrotic ectodermal dysplasia","volume":"134","author":"Hermes","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1124\/jpet.118.256040","article-title":"Prenatal treatment of X-linked hypohidrotic ectodermal dysplasia using recombinant ectodysplasin in a canine model","volume":"370","author":"Margolis","year":"2019","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_22","first-page":"483","article-title":"Workshop to identify critical windows of exposure for children's health: Immune and respiratory systems work group summary","volume":"108","author":"Dietert","year":"2000","journal-title":"Environ. Health Perspect."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1002\/bdrb.10035","article-title":"Species comparison of anatomical and functional immune system development","volume":"68","author":"Holsapple","year":"2003","journal-title":"Birth Defects Res. Part B Dev. Reprod. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/bdrb.10013","article-title":"Species comparison of anatomical and functional renal development","volume":"68","author":"Zoetis","year":"2003","journal-title":"Birth Defects Res. Part B Dev. Reprod. Toxicol."},{"key":"ref_25","first-page":"511","article-title":"Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models","volume":"108","author":"Rice","year":"2000","journal-title":"Environ. Health Perspect."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1111\/bcp.14301","article-title":"Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects","volume":"86","author":"Klein","year":"2020","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"18819","DOI":"10.1074\/jbc.M101280200","article-title":"Mutations leading to X-linked hypohidrotic ectodermal dysplasia affect three major functional domains in the tumor necrosis factor family member ectodysplasin-A","volume":"276","author":"Schneider","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1002\/pd.5384","article-title":"Reliability of prenatal detection of X-linked hypohidrotic ectodermal dysplasia by tooth germ sonography","volume":"39","author":"Hammersen","year":"2019","journal-title":"Prenat. Diagn."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Schmitz, D., Clarke, A., and Dondorp, W. (2018). Treatments and trials for the fetal patient: Imposing the burdens of enthusiasm?. The Fetus as a Patient: A Contested Concept and Its Normative Implications, Routledge. [1st ed.].","DOI":"10.4324\/9781315170749"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/1\/153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:00:54Z","timestamp":1760119254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/1\/153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,6]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["genes14010153"],"URL":"https:\/\/doi.org\/10.3390\/genes14010153","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,6]]}}}