Natural Exon Skipping Sets the Stage for Exon Skipping as Therapy for Dystrophic Epidermolysis Bullosa

Abstract

Dystrophic epidermolysis bullosa (DEB) is a devastating blistering disease affecting skin and mucous membranes. It is caused by pathogenic variants in the COL7A1 gene encoding type VII collagen, and can be inherited dominantly or recessively. Recently, promising proof-of-principle has been shown for antisense oligonucleotide (AON)-mediated exon skipping as a therapeutic approach for DEB. However, the precise phenotypic effect to be anticipated from exon skipping, and which patient groups could benefit, is not yet clear. To answer these questions, we studied new clinical and molecular data on seven patients from the Dutch EB registry and reviewed the literature on COL7A1 exon skipping variants. We found that phenotypes associated with dominant exon skipping cannot be distinguished from phenotypes caused by other dominant DEB variants. Recessive exon skipping phenotypes are generally relatively mild in the spectrum of recessive DEB. Therefore, for dominant DEB, AON-mediated exon skipping is unlikely to ameliorate the phenotype. In contrast, the overall severity of phenotypes associated with recessive natural exon skipping pivots toward the milder end of the spectrum. Consequently, we anticipate AON-mediated exon skipping for recessive DEB caused by bi-allelic null variants should lead to a clinically relevant improvement of this devastating phenotype.

Nonsequential Splicing Events Alter Antisense-Mediated Exon Skipping Outcome in COL7A1

“…Even more constructs would be necessary to evaluate the consequences of removing blocks of exons. While case reports suggest that the skipping of mutated exons in some patients results in less severe DEB [ 35 , 36 , 37 , 38 , 39 ], not every in-frame exon has been characterized in this manner. Hence, prioritization of amenable targets should be determined by those RDEB individuals with milder than anticipated phenotypes.…”

Personalized Development of Antisense Oligonucleotides for Exon Skipping Restores Type XVII Collagen Expression in Junctional Epidermolysis Bullosa

“…Regarding EB, AON-induced exon skipping has successfully been shown for frequently mutated exons 73, 80 and 105 of COL7A1 , and it is one out of various therapeutic approaches that are currently in development [ 6 , 7 , 33 , 34 , 35 ]. The fortunate fact that most of COL17A1 and COL7A1 exons are in frame and that several of them are dispensable for normal or sufficient protein function [ 36 , 37 ] has fueled the development of AON and exon skipping approaches primarily for the JEB and DEB subtypes of EB [ 35 , 36 , 38 , 39 ]. Considering RDEB, a clinical trial is currently ongoing using the exon 73 targeting AON QR-313 that will be applied onto EB wounds (NCT03605069) [ 33 ].…”

QR-313, an Antisense Oligonucleotide, Shows Therapeutic Efficacy for Treatment of Dominant and Recessive Dystrophic Epidermolysis Bullosa: A Preclinical Study

“…Topical application of AON could hold great potential for treatment of DDEB, due to the generally more localized and milder disease in this form of DEB. Treatment of DDEB, in which individuals carry one mutated allele and one wild-type allele, rises concerns for reduced functionality and/or dominant, diseaseaggravating negative effects from formation of wild-type and shortened polypeptides heterotrimers (Bremer et al 2019a). Thus, AONs were not initially considered as potential therapeutics for DDEB.…”

“…Thus far, work has focused on RDEB and little is known about the therapeutic potential of AONs for treatment of DDEB, although it represents around 40 % of DEB cases (Fine 2016). Recent natural history studies suggested no to even negative effects of exon-skipping for DDEB (Bremer et al 2019a). However, direct experimental assessment in a disease-relevant setting has not been performed.…”