Towards a Gene Therapy Clinical Trial for Epidermolysis Bullosa

Ferrari      Stefano; Pellegrini      Graziella; Matsui      Tatsuya; Mavilio      Fulvio; De   L.   Michele

Abstract

Genetic mutations affecting the capacity of basal keratinocytes to adhere firmly to the underneath derma lead to severe, often lethal, blistering disorders of the skin known as Epidermolysis Bullosa (EB). About 400000-500000 people worldwide are affected and no definitive treatments have yet been developed. Gene therapy might represent an alternative therapeutic approach for these devastating inherited disorders. In the last 10 years pre-clinical studies have shown that human epidermal stem cells can be stably transduced using integrating vectors allowing long-term genetic correction of the adhesion defects affecting EB keratinocytes both in vitro and in vivo after transplantation onto immunodeficient animals. In addition tremendous progress have been achieved in the clinical applications of cultured keratinocytes (cell therapy) for the regeneration of the epidermis over full thickness wounds or the restoration of damaged corneal surfaces. The combination of (i) optimised culturing conditions not altering the epidermal stemness, (ii) gene transfer vectors able to target epidermal stem cells very efficiently and (iii) surgical procedures allowing the grafting of large skin areas have therefore led our group to submit the first phase I/II gene therapy clinical trial for Junctional Epidermolysis Bullosa.

Keywords: Epidermolysis bullosa, Gene therapy, Keratinocyte, Stem cells

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