Introduction Combinatorial cell and gene therapies for life-threatening inherited skin disorders have shown tremendous potential for preclinical and clinical implementation with significant progress made for recessive dystrophic epidermolysis bullosa (RDEB). To date, various cell lineages including resident skin cells and adult stem cells have been investigated for gene and cell therapy for RDEB reaching the clinical trial stage. Sources of data Sources of data are key recent literature, ClinicalTrials.gov, Clinicaltrialsregister.eu and pharma press releases. Areas of agreement Cell-based gene transfer using autologous patients’ cells has demonstrated positive outcomes in preclinical and clinical trials and highlighted the importance of targeting resident skin stem cells to achieve a meaningful long-term effect. Additionally, adult stem cells, such as mesenchymal stromal cells, have the potential to ameliorate systemic manifestations of the disease. Areas of controversy While proven safe, the clinical trials of localized treatment have reported only modest and transient improvements. On the other hand, the risks associated with systemic therapies remain high and should be carefully weighed against the potential benefits. It is unclear to what extent adult stem cells can contribute to skin regeneration/wound healing. Growing points Further research is warranted in order to fulfil the potential of cellular therapies for RDEB. The development of combinatorial gene and cell-based approaches is required to achieve long-term clinical benefits. Areas timely for developing research Induced pluripotent stem cells can potentially provide a valuable source of autologous patient material for cellular therapies. In addition, recent advances in the field of gene editing can overcome hurdles associated with conventional gene addition approaches. Data Availability Statement No new data were generated or analysed in support of this review.

Genodermatoses constitute a clinically heterogeneous group of devastating genetic skin disorders. Currently, therapy options are largely limited to symptomatic treatments and although significant advances have been made in ex vivo gene therapy strategies, various limitations remain. However, the recent technical transformation of the genome editing field promises to overcome the hurdles associated with conventional gene addition approaches. In this review, we discuss the need for developing novel treatments and describe the current status of gene editing for genodermatoses, focusing on a severe blistering disease called epidermolysis bullosa (EB), for which significant progress has been made. Initial research utilized engineered nucleases such as transcription activator-like effector nucleases and meganucleases. However, over the last few years, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) have upstaged older generation gene editing tools. We examine different strategies for CRISPR/Cas9 application that can be employed depending on the type and position of the mutation as well as the mode of its inheritance. Promising developments in the field of base editing opens new avenues for precise correction of single base substitutions, common in EB and other genodermatoses. We also address the potential limitations and challenges such as safety concerns and delivery efficiency. This review gives an insight into the future of gene editing technologies for genodermatoses.

Base editing introduces precise single-nucleotide edits in genomic DNA and has the potential to treat genetic diseases such as the blistering skin disease recessive dystrophic epidermolysis bullosa (RDEB), which is characterized by mutations in the COL7A1 gene and type VII collagen (C7) deficiency. Adenine base editors (ABEs) convert A-T base pairs to G-C base pairs without requiring double-stranded DNA breaks or donor DNA templates. Here, we use ABE8e, a recently evolved ABE, to correct primary RDEB patient fibroblasts harboring the recurrent RDEB nonsense mutation c.5047 C > T (p.Arg1683Ter) in exon 54 of COL7A1 and use a next generation sequencing workflow to interrogate post-treatment outcomes. Electroporation of ABE8e mRNA into a bulk population of RDEB patient fibroblasts resulted in remarkably efficient (94.6%) correction of the pathogenic allele, restoring COL7A1 mRNA and expression of C7 protein in western blots and in 3D skin constructs. Off-target DNA analysis did not detect off-target editing in treated patient-derived fibroblasts and there was no detectable increase in A-to-I changes in the RNA. Taken together, we have established a highly efficient pipeline for gene correction in primary fibroblasts with a favorable safety profile. This work lays a foundation for developing therapies for RDEB patients using ex vivo or in vivo base editing strategies.

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Atopic dermatitis (AD) is a common chronic inflammatory skin disease that affects up to 20% of children and 10% of adults. AD is characterized by dry, itchy skin and recurring eczematous lesions, thought to be triggered by environmental factors in genetically susceptible individuals. Genetic variation has a high contribution to AD, with heritability estimates up to 90%. The major predisposing genetic factors for AD include loss-of-function variants in filaggrin (FLG) gene that lead to epidermal barrier dysfunction, and variants in immune regulatory genes, such as interleukin-13 (IL13). To identify further genetic factors of AD, we conducted a fixed-effects meta-analysis of five genome-wide association studies in 37,541 cases and 1,056,519 controls with data from FinnGen, UK Biobank, Estonian Biobank, EA-GLE Consortium, and BioBank Japan. We detected multiple associated loci of which 15 were not previously associated with AD. The novel loci comprise associations in basic helix-loophelix family member e40 (BHLHE40) and matrix metallopeptidase 12 (MMP12) genes with roles in variety of immune features, as an example. In a subgroup analysis of mild (patients treated with topical corticosteroids) and severe (treatment with tacrolimus, pimercolimus, cyclosporine and/or dubilumab) AD in the FinnGen data, we detected differing effect sizes for AD risk variants according to AD severity, with largest effect sizes for severe AD. In conclusion, we report novel genetic risk loci that associate with AD and report differing genetic architecture in mild vs. severe AD. Our findings complement the knowledge of the genetic background of AD and may underlay development of new treatment strategies.