TY - JOUR
T1 - Therapeutic prospects of exon skipping for epidermolysis bullosa
AU - Vermeer, Franciscus C.
AU - Bremer, Jeroen
AU - Sietsma, Robert J.
AU - Sandilands, Aileen
AU - Hickerson, Robyn P.
AU - Bolling, Marieke C.
AU - Pasmooij, Anna M.G.
AU - Lemmink, Henny H.
AU - Swertz, Morris A.
AU - Knoers, Nine V.A.M.
AU - van der Velde, K. Joeri
AU - van den Akker, Peter C.
N1 - Funding Information:
This work was sponsored by the Netherlands Organization for Health Research and Development (ZonMW) (Clinical Fellowship grant (90715614) to P.C.v.d.A.), DEBRA UK (Clinical Research Fellowship grant to P.C.v.d.A., R.P.H., A.S.), the Dutch Butterfly Child Foundation (Stichting Vlinderkind) (research grant to P.C.v.d.A., J.B., M.C.B.), Dutch Rare Diseases foundation (ZZF) (Research grant to A.M.G.P., P.C.v.d.A.). J.B. is part of COST Action CA17103 (https://www.antisenserna.eu). This project has also received funding from the Netherlands Organization for Scientific Research under NWO VIDI grant number 917.164.455 and European Union? s Horizon 2020 research and innovation programme under EJP RD COFUND-EJP N? 825575 (to M.A.S., K.J.v.d.V.).
Publisher Copyright:
© 2021 by the authors. 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/).
PY - 2021/11/12
Y1 - 2021/11/12
N2 - 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.
AB - 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.
KW - Antisense oligonucleotide
KW - Epidermolysis bullosa
KW - Exon skipping
UR - http://www.scopus.com/inward/record.url?scp=85118850113&partnerID=8YFLogxK
U2 - 10.3390/ijms222212222
DO - 10.3390/ijms222212222
M3 - Review article
C2 - 34830104
AN - SCOPUS:85118850113
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 22
M1 - 12222
ER -