Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 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. Key PointsRemarkable 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.

Profiling trial burden and patients’ attitudes to improve clinical research in epidermolysis bullosa

“…The number of innovative local or systemic treatment modalities is constantly growing, including approaches of protein, cell and gene therapy as well as symptom-relieving therapies targeting key mediators of aberrant molecular pathways [4]. In addition there is a steady increase in the number of investigational products, which are currently being tested in clinical trials [5][6][7].…”

Translational perspectives to treat Epidermolysis bullosa—Where do we stand?

“…This means involving affected individuals and their caregivers in decisions on study length and portfolio, target population, in-/exclusion criteria, definition of clinically meaningful endpoints, appropriate timing of outcome assessments, as well as information policies, including timely disclosure of trial results. Patient-centricity aims at reducing TA B L E 1 Emerging and ongoing clinical trials and therapeutic approaches for Epidermolysis bullosa [9,22] the patients' trial burden, for example in terms of time, travel, number of scheduled visits, literacy, personal financial expenditures, and compatibility with occupational obligations, and importantly, extent of invasive investigations on highly fragile, chronically wounded skin.…”

“…The spectrum comprises of corrective and symptom-relieving therapies, including innovative therapeutic components from the bench, repurposed drugs approved for other (more common) diseases like cancers or immune disorders, as well as strategies for gene-, protein-, cell-based and small molecule therapies. [7][8][9]…”

Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa

“…In this context, a consensus in the EB expert community on the complementarity of different therapeutic approaches to optimize treatment outcomes was recently reported, involving e.g. pain-relieving drugs such as opioids with non-pharmacological interventions [88,89].…”