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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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Autores principales: Schneider, Holm, Hadj-Rabia, Smail, Faschingbauer, Florian, Bodemer, Christine, Grange, Dorothy K., Norton, Mary E., Cavalli, Riccardo, Tadini, Gianluca, Stepan, Holger, Clarke, Angus, Guillén-Navarro, Encarna, Maier-Wohlfart, Sigrun, Bouroubi, Athmane, Porte, Florence
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9858920/
https://www.ncbi.nlm.nih.gov/pubmed/36672894
http://dx.doi.org/10.3390/genes14010153
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author Schneider, Holm
Hadj-Rabia, Smail
Faschingbauer, Florian
Bodemer, Christine
Grange, Dorothy K.
Norton, Mary E.
Cavalli, Riccardo
Tadini, Gianluca
Stepan, Holger
Clarke, Angus
Guillén-Navarro, Encarna
Maier-Wohlfart, Sigrun
Bouroubi, Athmane
Porte, Florence
author_facet Schneider, Holm
Hadj-Rabia, Smail
Faschingbauer, Florian
Bodemer, Christine
Grange, Dorothy K.
Norton, Mary E.
Cavalli, Riccardo
Tadini, Gianluca
Stepan, Holger
Clarke, Angus
Guillén-Navarro, Encarna
Maier-Wohlfart, Sigrun
Bouroubi, Athmane
Porte, Florence
author_sort Schneider, Holm
collection PubMed
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 (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/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.
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spelling pubmed-98589202023-01-21 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 Schneider, Holm Hadj-Rabia, Smail Faschingbauer, Florian Bodemer, Christine Grange, Dorothy K. Norton, Mary E. Cavalli, Riccardo Tadini, Gianluca Stepan, Holger Clarke, Angus Guillén-Navarro, Encarna Maier-Wohlfart, Sigrun Bouroubi, Athmane Porte, Florence Genes (Basel) Study Protocol 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/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. MDPI 2023-01-06 /pmc/articles/PMC9858920/ /pubmed/36672894 http://dx.doi.org/10.3390/genes14010153 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Study Protocol
Schneider, Holm
Hadj-Rabia, Smail
Faschingbauer, Florian
Bodemer, Christine
Grange, Dorothy K.
Norton, Mary E.
Cavalli, Riccardo
Tadini, Gianluca
Stepan, Holger
Clarke, Angus
Guillén-Navarro, Encarna
Maier-Wohlfart, Sigrun
Bouroubi, Athmane
Porte, Florence
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 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 Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9858920/
https://www.ncbi.nlm.nih.gov/pubmed/36672894
http://dx.doi.org/10.3390/genes14010153
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