Dystrophic epidermolysis bullosa (RDEB) is an inherited skin disease that causes fragile skin. RDEB is caused by mutations in the gene that encoded a protein called type VII collagen. Because collagen is a major structural component of skin, collagen mutations result in fragile skin and mucous membranes that blister easily if they are subjected to even slight mechanical stresses. There are no cures for such diseases, but skin creams and palliative care can decrease the severity of the symptoms.
Induced pluripotent stem cells (iPSCs) have the ability to treat such genetic diseases. In order to provide proof of principle of the applicability of iPSCs for the treatment of RDEB, Daniel Wenzel and his colleagues in the laboratory of Arabella Meixner from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, Austria made iPSCs from mice that harbored mutations in the gene that encodes type VII collagen (Col7a1) and exhibited skin fragility and blistering. The symptoms displayed by these Col7a1-mutant mice resembled human RDEB.
Wenzel and his coworkers then genetically repaired the Col7a1 mutations in these iPSCs, and then differentiated these cells into functional fibroblasts that expressed and secreted normal type VII collagen. When implanted, the genetically-repaired iPSC–derived fibroblasts did not form tumors, and could be successfully traced up to 16 weeks after intradermal injection. Therapy with iPSC-derived fibroblasts also resulted in faithful and long-term restoration of type VII collagen deposition at the epidermal-dermal junction of Col7a1 mutant mice, and restored the resistance of the skin to mechanical stresses.
Thus, intradermal injection of genetically repaired iPSC-derived fibroblasts restored the mechanical resistance of the skin to blistering in RDEB mice. These data demonstrate that, at least in principle, RDEB skin can be effectively and safely repaired using a combination of gene therapy and iPSC-based cell therapy.
A similar study examined another type of epidermolysis bullosa. Noriko Umegaki-Arao and her colleagues in the laboratory of Angela Christiano from Columbia University used iPSCs to treat mice with a distinct type of epidermolysis bullosa that resulted from mutations in COL17A1 gene, which encodes type XVII collagen (Col17). In this case, however, the mutation has been observed to revert or fix itself in patients. Patients tend to have patches of skin that are normal in a sea of abnormal skin.
Therefore, Umegaki-Arao and her coworkers derived iPSCs from Col17-mutant mice, differentiated them into skin cells (keratinocytes) and then cultured them, examining individual clones for reversion to normal Col17, which was fairly easy to do as it turns out. Once revertant-iPSC keratinocytes were properly secured, and then used them to reconstitute human skin in mutant mice. Thus, revertant keratinocytes can be a viable source of spontaneously gene-corrected cells for developing iPSC-based therapeutic approaches in the treatment of epidermolysis bullosa.