Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020

Molecular Diagnosis & Therapy https://doi.org/10.1007/s40291-020-00466-7 REVIEW ARTICLE Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020 Cristina Has1 · Andrew South2 · Jouni Uitto2 © The Author(s) 2020 Abstract Epidermolysis bullosa (EB) is a group of rare genetic disorders for which significant progress has been achieved in the development of molecular therapies in the last few decades. Such therapies require knowledge of mutant genes and specific mutations, some of them being allele specific. A relatively large number of clinical trials are ongoing and ascertaining the clinical efficacy of gene, protein or cell therapies or of repurposed drugs, mainly in recessive dystrophic EB. It is expected that some new drugs may emerge in the near future and that combinations of different approaches may result in improved treatment outcomes for individuals with EB. 1 Introduction Epidermolysis bullosa (EB) comprises a group of genetic disorders characterized by fragility of the skin and mucosal membranes. The molecular basis involves pathogenic variants in genes encoding structural proteins of the dermal–epidermal junction zone (DEJZ) [1]. As a consequence of missing or dysfunctional molecules (e.g., keratins 5/14, integrin α6β4, type XVII and VII collagens), reduced epidermal–dermal cohesion results in blisters after minimal mechanical trauma. The clinical severity of EB covers a broad spectrum, ranging from minor skin or nail involvement and minimal disease burden in localized subtypes to early lethality or life-long progressive systemic disease in severe subtypes [2]. EB is a prototypic disorder for which molecular therapies have been under development in the last few decades. Significant progress has been achieved in understanding the molecular pathogenesis of EB and the potential Cristina Has and Andrew South contributed equally. * Cristina Has cristina.has@uniklinik‑freiburg.de 1 Department of Dermatology, Faculty of Medicine, University of Freiburg, Hauptstr. 7, 79104 Freiburg, Germany 2 Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and The Joan and Joel Rosenbloom Research Center for Fibrotic Diseases, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA Key Points Remarkable progress has been made in understanding the molecular genetics and underlying pathomechanisms of epidermolysis bullosa (EB) forming the platform for development of treatments. Gene-replacement approaches, particularly delivery of COL7A1 to the skin of patients with severe dystrophic EB, type VII collagen replacement, skipping of exons and read-through of premature termination codons are currently in clinical trials. Preclinical research explores the applicability of new strategies in regenerative medicine (e.g., induced pluripotent stem cells) and genome editing (e.g., CRISPR/ Cas9). Particular effort is focused on severe dystrophic EB, characterized by extensive scarring and aggressive squamous cell carcinomas. Small molecules repurposed to reduce fibrosis, and the multikinase inhibitor rigosertib—for the treatment of recessive dystrophic EB squamous cell carcinomas—are being tested in clinical trials. Vol.:(0123456789) C. Has et al. benefits and limitations of different therapeutic approaches [3]. Considering that EB is a rare disease, a relatively large number of clinical trials are ongoing and ascertaining the clinical efficacy of gene, protein or cell therapies or of repurposed drugs (Table 1). In parallel, preclinical research explores the applicability of new strategies in regenerative medicine (e.g., induced pluripotent stem cells [iPSCs]) and genome editing (e.g., CRISPR/Cas9) (Table 2). However, the initial hope of rapid translation from bench to bedside has been tempered by multiple hurdles and challenges, including the complexity of EB itself. Thus, instead of attempting to cure EB, researchers are increasingly aiming at “symptom-relieving” or “diseasemodifying” therapies. 2 Molecular Pathology of Epidermolysis Bullosa (EB) Pathogenic variants in 16 genes cause the four main subtypes of classical EB: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB) and Kindler EB; over 30 EB subtypes are further defined based on clinical and molecular criteria [2]. EBS and JEB are genetically heterogeneous, whereas DEB and Kindler EB are caused by mutations in single genes, COL7A1 and FERMT1, respectively. In addition to the classical forms of EB, five additional genes have been associated with skin fragility disorders in differential diagnosis of EB. Thus, a total of 21 genes are known to harbor mutations in skin fragility disorders in the spectrum of EB. The determinants of the EB phenotype include the identity of the affected gene/protein system and the specific nature of the disease-causing genetic variants. Specifically, residual amounts or functions of the affected protein versus its complete absence or loss-of-function determine whether the disease will be relatively mild, intermediate or severe. Examples of genotype–phenotype correlations in patients with JEB and DEB have shown that small amounts (even less than 10%) of proteins with partial function may result in a mild/intermediate phenotype [4–7]. Genetic and epigenetic disease modifiers may also play a modulating role but have only been experimentally demonstrated in a few cases [8–12], and such findings have to be extrapolated to larger numbers of patients to allow general conclusions. Socio-economic environment and access to medical care are also critical elements in determining the natural history of the disease and the development of complications in individual cases. Although multiple different proteins are affected, it is widely accepted that all EB types have life-long skin fragility in common and this pathology (disruption of the barrier function of the skin and mucous membranes) leads to chronic tissue damage and associated inflammation. Loss of epidermal integrity is accompanied by bacterial colonization and activation of mechanisms of innate and adaptive immunity. The cytokines engaged in the tissue damage/ repair processes depend on the extent of the mucocutaneous defects and on the level of blister formation (implying either cytolysis or basement membrane zone disruption), and include interleukin (IL)-1, IL-6 and transforming growth factor (TGF)-β [13–15]. With time, the ongoing regeneration processes affect the stem cells and the underlying connective tissue, leading to chronic, non-healing wounds. If these events affect a significant percentage of the body surface (such as more than 20–30% at any given time) over a long period, the “inflammation” becomes systemic, as shown by leukocytosis, increased C reactive protein and increased levels of immunoglobulins (IgG, IgM and IgA) [16]. In recessive DEB (RDEB), involvement of the oral and esophageal mucosa impairs feeding, and—together with the high (...truncated)