Cell therapy, gene therapy and tissue engineering have the potential to revolutionize the field of regenerative medicine. In particular, gene therapy is understood as the therapeutical correction of mutated genes by addition of a correct copy of the gene or site-specific gene modifications. Gene correction of somatic stem cells sustaining renewing tissues is critical to ensure long-term clinical success of ex vivo gene therapy. To date, remarkable clinical outcomes arose from combined ex vivo cell and gene therapy of different genetic diseases, such as immunodeficiencies and genodermatoses. Despite the efforts of researchers around the world, only few of these advanced approaches has yet made it to routine therapy. In fact, gene therapy poses one of the greatest technical challenges in modern medicine, spanning safety and efficacy issues, regulatory constraints, registration and market access, all of which need to be addressed to make the therapy available to rare disease patients. In this review, we survey at some of the main challenges in the development of combined cell and gene therapy of genetic skin diseases.

The epidermis is one of the largest tissues in the human body, serving as a protective barrier. The basal layer of the epidermis, which consists of epithelial stem cells and transient amplifying progenitors, represents its proliferative compartment. As keratinocytes migrate from the basal layer to the skin surface, they exit the cell cycle and initiate terminal differentiation, ultimately generating the suprabasal epidermal layers. A deeper understanding of the molecular mechanisms and pathways driving keratinocytes’ organization and regeneration is essential for successful therapeutic approaches. Single-cell techniques are valuable tools for studying molecular heterogeneity. The high-resolution characterization obtained with these technologies has identified disease-specific drivers and new therapeutic targets, further promoting the advancement of personalized therapies. This review summarizes the latest findings on the transcriptomic and epigenetic profiling of human epidermal cells, analyzed from human biopsy or after in vitro cultivation, focusing on physiological, wound healing, and inflammatory skin conditions.

Epidermolysis bullosa (EB) is a devastating genetic skin disease typified by a plethora of different phenotypes and ranking from severe, early lethal, to mild localized forms. Although there is no cure for EB, recent progress in pharmacology and molecular and cellular biology is boosting the development of new advanced therapeutic strategies. Here we will focus on two main categories of such therapies: (1) those aimed at controlling inflammation and inducing reepithelialization of the wounds, and (2) those, perhaps more challenging and ambitious, that aim to permanently regenerate a fully functional epidermis, which requires targeting of epidermal stem cells. In both cases, the genetic variants underlying the different EB forms and factors, such as genetic background, modifier genes, comorbidities, and lifestyle, all of which impinge on EB genotype-phenotype correlation, need to be defined.I nherited epidermolysis bullosa (EB) is characterized by recurrent blistering of stratified epithelia. EB is caused by more than 1000 mutations in at least 16 structural genes encoding proteins forming hemidesmosomes and anchoring fibrils, which are essential for the integrity of the epidermal-dermal junction (Has et al. 2020a). Blisters arise spontaneously or upon minimal trauma as the result of the fragility of skin and mucous membranes. Common features of many EB forms include damage of ocular surface, upper airways, oral mucosa and gastrointestinal and renal systems, as well as hair, nail, and enamel defects (Bardhan et al. 2020;Has et al. 2020a). Incidence and prevalence of EB in the United States are 11.1 per one million people and 19.6 per one million live births, respectively. Similar values have been reported in Europe (Fine 2010;Has et al. 2020a). EB affects individuals from all ethnic origins regardless of gender and displays either dominant or recessive patterns of inheritance. EB phenotypes range from mild, localized blistering to massive blistering, erosions and chronic wounds. Severe EB forms can be early lethal and generalized EB frequently leads to aggressive squamous cell carcinoma (SCC) (Condorelli et al. 2019;Bardhan et al. 2020).