Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types....

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Autores principales:	Franciscus C. Vermeer, Jeroen Bremer, Robert J. Sietsma, Aileen Sandilands, Robyn P. Hickerson, Marieke C. Bolling, Anna M.G. Pasmooij, Henny H. Lemmink, Morris A. Swertz, Nine V.A.M. Knoers, K. Joeri van der Velde, Peter C. van den Akker
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	epidermolysis bullosa exon skipping antisense oligonucleotide Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/1311e30c58c5407bb9cef31de25b8743
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spelling	oai:doaj.org-article:1311e30c58c5407bb9cef31de25b87432021-11-25T17:54:28ZTherapeutic Prospects of Exon Skipping for Epidermolysis Bullosa10.3390/ijms2222122221422-00671661-6596https://doaj.org/article/1311e30c58c5407bb9cef31de25b87432021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12222https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.Franciscus C. VermeerJeroen BremerRobert J. SietsmaAileen SandilandsRobyn P. HickersonMarieke C. BollingAnna M.G. PasmooijHenny H. LemminkMorris A. SwertzNine V.A.M. KnoersK. Joeri van der VeldePeter C. van den AkkerMDPI AGarticleepidermolysis bullosaexon skippingantisense oligonucleotideBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12222, p 12222 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	epidermolysis bullosa exon skipping antisense oligonucleotide Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	epidermolysis bullosa exon skipping antisense oligonucleotide Biology (General) QH301-705.5 Chemistry QD1-999 Franciscus C. Vermeer Jeroen Bremer Robert J. Sietsma Aileen Sandilands Robyn P. Hickerson Marieke C. Bolling Anna M.G. Pasmooij Henny H. Lemmink Morris A. Swertz Nine V.A.M. Knoers K. Joeri van der Velde Peter C. van den Akker Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
description	Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.
format	article
author	Franciscus C. Vermeer Jeroen Bremer Robert J. Sietsma Aileen Sandilands Robyn P. Hickerson Marieke C. Bolling Anna M.G. Pasmooij Henny H. Lemmink Morris A. Swertz Nine V.A.M. Knoers K. Joeri van der Velde Peter C. van den Akker
author_facet	Franciscus C. Vermeer Jeroen Bremer Robert J. Sietsma Aileen Sandilands Robyn P. Hickerson Marieke C. Bolling Anna M.G. Pasmooij Henny H. Lemmink Morris A. Swertz Nine V.A.M. Knoers K. Joeri van der Velde Peter C. van den Akker
author_sort	Franciscus C. Vermeer
title	Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
title_short	Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
title_full	Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
title_fullStr	Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
title_full_unstemmed	Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
title_sort	therapeutic prospects of exon skipping for epidermolysis bullosa
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1311e30c58c5407bb9cef31de25b8743
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Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa

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