University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, The Netherlands.
University of Groningen, University Medical Center Groningen, Department of Dermatology, 9700 RB Groningen, The Netherlands.
Int J Mol Sci. 2021 Nov 12;22(22):12222. doi: 10.3390/ijms222212222.
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.
大疱性表皮松解症是一组遗传性皮肤疾病，其特征为各种基因中的致病性变异导致皮肤（和黏膜）脆弱。疾病严重程度范围从最严重类型的儿童早期死亡到最轻微类型的偶尔肢端水疱。EB 的亚型和严重程度与涉及的基因以及该基因中的特定变异有关，这也决定了其遗传方式。目前的治疗主要集中在对症治疗，如伤口护理和水疱预防，因为真正的治愈治疗方法仍处于临床前阶段。鉴于目前的理解水平，EB 所涉及的基因和变异的广泛范围使得不可能为所有患者制定单一的治疗策略。很可能需要许多不同的针对变异的治疗策略，最终才能治疗所有患者。反义寡核苷酸（ASO）介导的外显子跳跃旨在通过从前信使 RNA 中去除突变外显子来恢复开放阅读框，从而对抗致病序列变异。这应该会导致缺失的蛋白在受影响的皮肤中得到恢复产生，从而改善表型。几项临床前研究表明，外显子跳跃可以在体外、皮肤等效物和源自 EB 患者皮肤细胞的皮肤移植物中恢复蛋白产生，表明 ASO 介导的外显子跳跃可能是一种可行的策略，可作为局部或系统治疗。外显子跳跃对 EB 的潜在价值得到了一项研究的支持，该研究表明，携带导致自然外显子跳跃的变异的患者的表型严重程度降低。在本文中，我们回顾了过去 15 年中外显子跳跃在 EB 方面取得的重大进展，并强调了这种基于 RNA 的治疗方法的机会和当前挑战。此外，我们根据所有涉及 EB 的基因的基因组信息提出了外显子跳跃开发的优先级策略。
