From marrow to matrix: novel gene and cell therapies for epidermolysis bullosa

Abstract

Epidermolysis bullosa encompasses a group of inherited connective tissue disorders that range from mild to lethal. There is no cure, and current treatment is limited to palliative care that is largely ineffective in treating the systemic, life-threatening pathology associated with the most severe forms of the disease. Although allogeneic cell- and protein-based therapies have shown promise, both novel and combinatorial approaches will undoubtedly be required to totally alleviate the disorder. Progress in the development of next-generation therapies that synergize targeted gene-correction and induced pluripotent stem cell technologies offers exciting prospects for personalized, off-the-shelf treatment options that could avoid many of the limitations associated with current allogeneic cell-based therapies. Although no single therapeutic avenue has achieved complete success, each has substantially increased our collective understanding of the complex biology underlying the disease, both providing mechanistic insights and uncovering new hurdles that must be overcome.

Figure 1

Images of patient wounds on the right foot pretransplant and again at day 145. Data taken from ref. .

Figure 2

Potential strategies to implement next-generation therapies in the treatment of recessive dystrophic epidermolysis bullosa. In this diagram, mutant or naturally gene-reverted cells are isolated from the patient, and mutant cells are gene corrected. These cells are then either used directly or reprogrammed in to induced pluripotent stem cells (iPSCs). If gene correction of primary cells is not possible, the gene correction step can be performed at the iPSC stage. The gene-corrected iPSCs are subsequently differentiated into hematopoietic stem/progenitor cells and/or mesenchymal stem cells for systemic administration, or keratinocytes and/or fibroblasts for localized application.

Figure 3

Teratoma immunofluorescence shows the dermal-epidermal junction indicated with white arrows. The immunofluorescence markers are as follows: blue, 4′,6-diamidino-2-phenylindole (DAPI) nuclear stain; green, cytokeratin 5; and red, type VII collagen. Images are representative images from at least three animals. Antibody staining was performed from a single master mix on the same day using identical microscopy settings. Data taken from ref. .