Abstract and Introduction
Epidermolysis bullosa (EB) encompasses a heterogeneous group of inherited skin fragility disorders, with mutations in genes encoding the basement membrane zone (BMZ) proteins that normally ensure dermal–epidermal integrity. Of the four main EB types, recessive dystrophic EB (RDEB), especially the severe variant, represents one of the most debilitating clinical entities, with recurrent mucocutaneous blistering and ulceration leading to chronic wounds, infections, inflammation, scarring and ultimately cutaneous squamous cell carcinoma, which leads to premature death. Improved understanding of the molecular genetics of EB over the past three decades and advances in biotechnology have led to rapid progress in developing gene and cell-based regenerative therapies for EB. In particular, RDEB is at the vanguard of advances in human clinical trials of advanced therapeutics. Furthermore, the past decade has witnessed the emergence of a real collective, global effort involving academia and industry, supported by international EB patient organizations such as the Dystrophic Epidermolysis Bullosa Research Association (DEBRA), among others, to develop clinically relevant and marketable targeted therapeutics for EB. Thus, there is an increasing need for the practising dermatologist to become familiar with the concept of gene therapy, fundamental differences between various approaches, and their human applications. This review explains the principles of different approaches of gene therapy, summarizes its journey, and discusses its current and future impact in RDEB.
Inherited epidermolysis bullosa (EB) encompasses a clinically and genetically diverse group of skin fragility disorders that ranges from a few localized blisters of the skin to large areas of chronic wounds affecting both skin and mucosa with systemic complications.[1–3] Of the four EB types – simplex, junctional (JEB), dystrophic (DEB) and Kindler – caused by mutations in genes encoding the basement membrane zone (BMZ) proteins, the recessive form of DEB (RDEB) represents one of the most debilitating variants, with significant disease and psychosocial burden on both patients and their families.[1–3] These individuals often have recurrent skin and mucosal blisters and erosions that evolve into chronic wounds, inflammation, infections, scarring and cutaneous squamous cell carcinomas (SCCs) with high metastatic potential, thus leading to premature death. Epidemiological data on EB are variable across countries but the latest report by the Dutch EB Registry indicates for RDEB an incidence of 5·5 cases per million live births, and a prevalence of 2·1 cases per million population.
RDEB is caused by mutations in COL7A1, which encodes the collagen alpha-1(VII) chain (C7), the main constituent of anchoring fibrils (AFs) that attach the epidermis to the dermis. Thus, in individuals with RDEB the epidermis very easily detaches from the dermis, even with the slightest shearing force. In the face of such a significant disease burden, management is currently supportive, involving a multidisciplinary team. Recent years have witnessed a collective global effort in search of effective therapies for RDEB through partnerships between academia, industry, EB charities and patients. Emerging therapies for RDEB include cell therapy,[5–9] gene therapy[10–13] and protein replacement therapy,[14–16] and repurposed drugs such as gentamicin, losartan and those targeting inflammation such as dupilumab. Gene therapy has been at the forefront of such advanced therapeutics, and various forms of novel techniques have been rapidly emerging over the past two decades.
This review (i) explains the principles underlying different approaches of gene therapy; (ii) summarizes various approaches of gene therapy developed for RDEB and challenges in clinical translation; and (iii) lays out clinical perspectives of gene therapy for RDEB.
The British Journal of Dermatology. 2022;186(4):609-619. © 2022 Blackwell Publishing