Epidermolysis bullosa (EB) is a major, rare disease of the skin that in extreme cases can be fatal. The symptoms of EB are life-long and include mechanically-induced blistering, chronic wounds, perturbed wound healing, pain, secondary infections, alopecia, loss of nails, scarring and fibrosis. The disease manifests with a very broad spectrum of severity and presentations. The main subtypes comprise simplex EB, junctional EB, dystrophic EB and kindler EB. To date pathogenetic variants have been recognised in >20 genes. The severe forms have a very high unmet medical need, and evidence-based therapies are urgently needed.
As with other genetic diseases, a number of new approaches to treatment are under investigation.
These include curative approaches (e.g. gene therapy, protein and RNA-based therapies), regenerative approaches (use of somatic cells, mesenchymal stem cells, bone marrow transplantation) and disease modifying approaches (small molecules and biologicals).
Among these, ex vivo keratinocyte gene therapy has been used for EB for more than 13 years.
In this technique, cultured keratinocyte stem cells, known as holoclones, generate sheets of epithelium used to restore severe skin defects.
In a recent investigation, topical and intradermal gentamicin was shown to suppress nonsense mutations and induces type VII collagen and anchoring fibrils in EB patients.
Gentamicin therapy may thus provide a readily available treatment for RDEB patients with nonsense mutations.
Difference types of keratinocyte gene therapy have been investigated in EB using either a retroviral vector or gene editing with CRISPR/Cas9. [1-3]
This latter technique has been shown to be efficient in a mouse model, and is thus a promising strategy.
HSV-1-based gene delivery targeting keratinocytes through topical delivery is also under study.
Another group has demonstrated that one or two subcutaneous injections of antisense oligoribonucleotides at doses ranging from 400 μg up to 1 mg restored type VII collagen expression and anchoring fibril formation in vivo in a xenograft model of recessive dystrophic epidermolysis bullosa skin equivalent. 
In a ground-breaking procedure, autologous transgenic keratinocyte cultures were demonstrated to have the capacity to regenerate an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of EB. 
The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection.
Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes.
Presented by: Prof. Kristian Reich, Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, and Skinflammation® Center, Hamburg, Germany