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
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 hyperth...
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MDPI AG
2023-01-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/1/153 |
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| author | Holm Schneider Smail Hadj-Rabia Florian Faschingbauer Christine Bodemer Dorothy K. Grange Mary E. Norton Riccardo Cavalli Gianluca Tadini Holger Stepan Angus Clarke Encarna Guillén-Navarro Sigrun Maier-Wohlfart Athmane Bouroubi Florence Porte |
| author_facet | Holm Schneider Smail Hadj-Rabia Florian Faschingbauer Christine Bodemer Dorothy K. Grange Mary E. Norton Riccardo Cavalli Gianluca Tadini Holger Stepan Angus Clarke Encarna Guillén-Navarro Sigrun Maier-Wohlfart Athmane Bouroubi Florence Porte |
| author_sort | Holm Schneider |
| collection | DOAJ |
| description | 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 (<i>EDA</i>). Most affected males are hemizygous for <i>EDA</i> 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/NFκB 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. |
| first_indexed | 2024-03-09T12:35:37Z |
| format | Article |
| id | doaj.art-21ee04deb4b04402a680f6fa142eb454 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T12:35:37Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
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| series | Genes |
| spelling | doaj.art-21ee04deb4b04402a680f6fa142eb4542023-11-30T22:24:22ZengMDPI AGGenes2073-44252023-01-0114115310.3390/genes14010153Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal DysplasiaHolm Schneider0Smail Hadj-Rabia1Florian Faschingbauer2Christine Bodemer3Dorothy K. Grange4Mary E. Norton5Riccardo Cavalli6Gianluca Tadini7Holger Stepan8Angus Clarke9Encarna Guillén-Navarro10Sigrun Maier-Wohlfart11Athmane Bouroubi12Florence Porte13Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, GermanyDepartment of Dermatology, Reference Centre for Genodermatoses and Rare Skin Diseases (MAGEC), Hopital Universitaire Necker-Enfants Malades, Assistance Publique—Hospitals of Paris, University of Paris-Cité, 75743 Paris, FranceDepartment of Obstetrics and Gynecology, University Hospital Erlangen, 91054 Erlangen, GermanyDepartment of Dermatology, Reference Centre for Genodermatoses and Rare Skin Diseases (MAGEC), Hopital Universitaire Necker-Enfants Malades, Assistance Publique—Hospitals of Paris, University of Paris-Cité, 75743 Paris, FranceDepartment of Pediatrics, Division of Genetics and Genomic Medicine, Washington University, St. Louis, MO 63110, USADepartment of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA 94143, USAPediatric Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, 20122 Milan, ItalyPediatric Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Clinical Sciences and Community Health, 20122 Milan, ItalyDepartment of Obstetrics, University Hospital Leipzig, 04103 Leipzig, GermanyInstitute of Medical Genetics, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF10 3AT, UKMedical 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, SpainCenter for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, GermanyPierre Fabre Médicament, 31100 Toulouse, FranceEspeRare Foundation, 1202 Geneva, SwitzerlandX-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 (<i>EDA</i>). Most affected males are hemizygous for <i>EDA</i> 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/NFκB 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.https://www.mdpi.com/2073-4425/14/1/153ectodermal dysplasiasweat glandsanhidrosisectodysplasin Aprotein replacementfetal therapy |
| spellingShingle | Holm Schneider Smail Hadj-Rabia Florian Faschingbauer Christine Bodemer Dorothy K. Grange Mary E. Norton Riccardo Cavalli Gianluca Tadini Holger Stepan Angus Clarke Encarna Guillén-Navarro Sigrun Maier-Wohlfart Athmane Bouroubi Florence Porte 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 Genes ectodermal dysplasia sweat glands anhidrosis ectodysplasin A protein replacement fetal therapy |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | ectodermal dysplasia sweat glands anhidrosis ectodysplasin A protein replacement fetal therapy |
| url | https://www.mdpi.com/2073-4425/14/1/153 |
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