To most of us, blisters are a mild and short-lived annoyance; we curse the badly-fitting shoe, gingerly apply a plaster then hobble on with our daily activities. Now, imagine instead that the skin over your entire body is fragile and prone to rapid blistering. Minor trauma – anything from bumping your elbow to friction from a t-shirt with raised seams – causes blistering and erosion of your skin, rendering you vulnerable to infection.
To add insult to literal injury, your mucous membranes are similarly affected: the simple act of brushing your teeth gives you mouth ulcers, and eating anything apart from the softest foods is impossible for fear of further injuring and narrowing your oesophagus. These and other debilitating symptoms characterise Herlitz Junctional Epidermolysis Bullosa, a condition described by the charity DEBRA as the ‘worst disease you’ve never heard of’ (http://www.debra.org/whatiseb; accessed December 2017).
Herlitz Junctional Epidermolysis Bullosa, or H-JEB, is a rare and often lethal genetic condition that has an estimated infant mortality rate of over 70% (Kelly-Mancuso et al. 2014). Blistering arises due to an inherent fragility of the skin and mucous membranes, caused by mutations in genes (LAMA3, LAMB3 or LAMC2) that jointly encode an essential glycoprotein component of basement membranes. This glycoprotein, known as laminin-332, plays a critical role in anchoring skin cells to the basement membrane; without laminin-332, the outer layer of skin (or epidermis) is not properly connected to the underlying dermis. This means that any action which causes friction leads to separation of the epidermis from the dermis – hence blisters, open wounds and almost intolerable amounts of pain.
There is currently no cure for H-JEB and therapies are mainly palliative, most closely resembling treatments used for severe burn victims. Against this harrowing clinical backdrop, Hirsch et al. 2017 report on a ground-breaking advance that may herald the start of a new era in H-JEB treatment.
In their Nature article, Hirsch et al. 2017 describe the case of a 7-year old Syrian H-JEB patient (LAMB3 mutation) who presented with epidermal loss on over 60% of his total body surface area. The authors took a 4cm-square skin biopsy from an unaffected area, from which they isolated primary skin cells (also known as keratinocytes). Collaborators based in Modena, Italy used a retroviral gene therapy vector to deliver a correct copy of LAMB3 to the patient’s keratinocytes, which, once corrected, were grown and cultured into >8000cm2 of skin graft sheets. Now comes the astonishing part. Over three successive surgeries, these skin grafts were used to repair the areas of the patient’s body that lacked an epidermis; in total, 80% of his total body surface area was re-covered.
Remarkably, clinical follow-up showed that the regenerated, virally-corrected skin had firmly grafted onto the underlying dermis, healed normally and did not blister. Punch biopsies of the corrected epidermis showed normal skin architecture, with high expression of laminin-332. One of the major risks associated with retroviral gene therapy vectors is insertional oncogenesis, which arises when vector sequences integrate and activate genes (‘oncogenes’) that drive tumour development. Crucially, vector integration studies confirmed that the vector had inserted its DNA distant from oncogenes, demonstrating the safety of this gene therapy approach.
Of particular interest to scientists and clinicians studying skin turnover, the authors observed that a few long-lived stem cells (called ‘holoclones’) were responsible for the continued renewal of the corrected skin. Most importantly, the patient was discharged home four months after the first surgery with stable, robust skin that does not blister, itch or require ointment or medications. His name is Hassan, he loves football and, thanks to gene therapy, he can now play his favourite sport.
Hirsch, T., et al. (2017). “Regeneration of the entire human epidermis using transgenic stem cells.” Nature 551(7680): 327-332.
Kelly-Mancuso, G., et al. (2014). “Junctional epidermolysis bullosa incidence and survival: 5-year experience of the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA) nurse educator, 2007 to 2011.” Pediatr Dermatol 31(2): 159-162.