Genetically corrected iPSCs as cell therapy for recessive dystrophic epidermolysis bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in the gene encoding type VII collagen, resulting in fragile skin and mucous membranes that blister easily in response to mechanical stress. Induced pluripotent stem cells (iPSCs) carry the potential to fundamentally change cell-based therapies for human diseases, in particular for RDEB, for which no effective treatments are available. To provide proof of principle on the applicability of iPSCs for the treatment of RDEB, we developed iPSCs from type VII collagen (Col7a1) mutant mice that exhibited skin fragility and blistering resembling human RDEB. Genetically repaired iPSCs could be differentiated into functional fibroblasts that reexpressed and secreted type VII collagen. Corrected iPSC-derived fibroblasts did not form tumors in vivo and could be traced up to 16 weeks after intradermal injection. Moreover, iPSC-based cell therapy resulted in faithful and long-term restoration of type VII collagen deposition at the epidermal-dermal junction of Col7a1 mutant mice. Intradermal injection of genetically repaired iPSC-derived fibroblasts restored the mechanical resistance to skin blistering in mice with RDEB, suggesting that RDEB skin could be effectively and safely repaired using iPSC-based cell therapy.