Small-Molecule Therapies for Genetic Skin Fragility

Abstract

Of the known genetic skin diseases, dystrophic epidermolysis bullosa (DEB) is a prime target for therapy development. It is a monogenic, strongly disabling disorder with high unmet medical need. Lifelong generalized skin blistering as a consequence of minor mechanical friction, chronic wounds, excessive scarring, and progressive soft-tissue fibrosis are clinical hallmarks. Joint contractures and mitten deformities of the extremities cause severe disability, and the fibrosis of the skin increases tissue stiffness and favors development of aggressive squamous cell carcinoma, a feared complication of the disease.1 For obvious reasons, many investigators have pursued curative gene-, cell-, and protein-based therapy approaches for DEB, but these have turned out to be much more challenging than anticipated and have shown very limited benefit in pilot clinical trials.2 In the recent past, it has become clear that alternative approaches are urgently needed to improve the health and quality of life of severely affected patients. In line with this, Cogan et al.3 report in this issue on the use of aminoglycosides to induce readthrough of premature termination codons (PTCs) and to restore functional protein production in DEB keratinocytes and fibroblasts in vitro.