Clinical Perspectives of Gene-Targeted Therapies for Epidermolysis Bullosa

Abstract

New insights into molecular genetics and pathomechanisms in epidermolysis bullosa (EB), methodological and technological advances in molecular biology as well as designated funding initiatives and facilitated approval procedures for orphan drugs have boosted translational research perspectives for this devastating disease. This is echoed by the increasing number of clinical trials assessing innovative molecular therapies in the field of EB. Despite remarkable progress, gene-corrective modalities, aimed at sustained or permanent restoration of functional protein expression, still await broad clinical availability. This also reflects the methodological and technological shortcomings of current strategies, including the translatability of certain methodologies beyond preclinical models as well as the safe, specific, efficient, feasible, sustained and cost-effective delivery of therapeutic/corrective information to target cells. This review gives an updated overview on status, prospects, challenges and limitations of current gene-targeted therapies.

Keywords: Antisense oligonucleotides; Epidermolysis bullosa; Gene editing; Gene replacement; Gene therapy; Readthrough; Trans-splicing; siRNA.

Fig. 1

Clinical scope of epidermolysis bullosa (EB) subtypes. a Partly hemorrhagic blisters predominantly restricted to mechanically exposed acral sites in localized EB simplex. b Generalized skin involvement with characteristically grouped (“herpetiform”, c) blisters in severe EB simplex. d Widespread erosive skin denudation with crusting and inflammation in severe junctional EB. e Generalized blistering and chronic wounding with crusting and subsequent atrophic scarring in severe recessive dystrophic EB (RDEB). Oral manifestations in severe RDEB include (f) microstomia, enamel defects and excessive caries. g On mechanically exposed skin areas such as hands and feet, chronic acral scarring commonly leads to pseudosyndactily, nail loss and mitten deformity in severe RDEB. h Sites of repetitive tissue damage, chronic wounding and regeneration predispose to the development of aggressive cutaneous squamous cell carcinoma in severe RDEB. i EB naevi are large, eruptive irregularly pigmented and highly dynamic melanocytic lesions that typically arise in sites of previous bullae or erosions. Although clinical, dermatoscopic and histological features may be suggestive of melanoma, their course is usually benign. j Nail dystrophy, k milia formation and atrophic scarring are clinical hallmarks of dominant dystrophic EB

Fig. 2

Pathogenic traits in epidermolysis bullosa. Mutations in genes encoding components essential for the structural and functional integrity of the epidermis and dermo-epidermal junction underlie the four main types of epidermolysis bullosa (EB), featuring skin blistering within the epidermis (EB simplex), the lamina lucida (junctional EB), the upper dermis (DEB) or at mixed levels (Kindler EB). Letters in boxes next to the protein names indicate which subtype of EB results in case of non-functional or lacking protein (S EBS, J JEB, D DEB, K Kindler EB)