They propose gene correction of EB-causing mutations by gene editing. The brilliant approach represented by the work of Oro and colleagues is aimed at helping the majority of people with EB who do not have clinically identifiable mosaic cells (or in whom the gene reversion leads to only partial restoration of collagen expression).
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These advances are elegant and promising tools in future EB therapies, even though three key challenges remain: the iPSCs were generated with retroviral-mediated transgenesis, which is unlikely to be acceptable in clinical trials the skin-like equivalents are not true skin grafts and the graftable keratinocytes have not yet been tested in a murine model of EB.
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Now Christiano and colleagues have used keratinocytes with a naturally occurring reversion in the COL17A1 gene (encoding type XVII collagen) from a healthy appearing skin patch of an individual with JEB, reprogrammed them into iPSCs, and differentiated them into keratinocytes with the capacity to form skin-like organoids. Researchers have previously generated personalized iPSCs and iPSC-derived skin cells from individuals with JEB, RDEB and mosaic RDEB.
Revertant mosaicism occurs in some RDEB patients, providing a source of naturally gene-corrected skin cells.
This is a key observation, since previous work indicated that injection of cells or just a cell-free solution can also increase expression of mutant C7 at the epidermal-dermal junction in human RDEB subjects with hypomorphic COL7A1 mutations and improve wound healing, presumably in part by changing a chronic wound into an acute one.Įqually important to advances in the clinical application of iPSC therapy has been reprogramming keratinocytes, the major cell type expressing C7 in normal skin, with genetic reversion of the disease-causing mutations. To demonstrate functionality of the new C7, the authors tested the skin stability and observed it increased after injection of corrected fibroblasts, but not after administration of uncorrected mutant cells. Importantly, no obvious abnormal inflammatory response, fibrosis or tumor formation (such as teratoma derived from an errant iPSC, or squamous cell carcinoma (SCC) associated with the pathophysiology of RDEB) was observed over the 18 weeks after therapy. Expression of C7 increased over the first 8 weeks and then declined to the baseline levels expected in this model of RDEB (corresponding with the decline of donor cells to undetectable numbers over the same period). These corrected iPSCs were then differentiated back into fibroblasts, and injected intradermally into mutant mice. To demonstrate the feasibility of this iPSC-based therapy, mutant cells were corrected, restoring the function of Col7a1. The groups of Penninger and Bruckner-Tuderman used the latter model, and reprogrammed tail skin fibroblasts into iPSCs that were used for therapy. For RDEB, at least two murine models exist, one with no expression of basement membrane type VII collagen (C7), and one with approximately 10% wild-type expression of C7. Murine models have proven tremendously useful in studying the basic biology of human inherited skin diseases and in preclinical modeling of potential therapeutic interventions.
However, as the work from three teams discussed herein demonstrates, scientists are working with determination and creativity on a cure. Despite the intense efforts of medical scientists around the globe, there is currently no cure. EB is a horrible and frequently fatal disease that wrecks any attempt at a normal life, both for the sufferer and for the family. This disorder has an impact far beyond the skin, as these individuals experience severe skin blistering, corneal erosions, and mucosal wounds that can result in malnutrition.
Patients with these disorders are often called ‘butterfly children’ because of their delicate and easily damaged skin, and the fact that many do not survive into adulthood. The most overwhelming of these skin conditions are recessive dystrophic EB (RDEB) and junctional EB (JEB), autosomal recessive disorders in which the genes encoding major skin adhesion proteins do not function properly, leading to severely diminished or absent gene expression. In the severe forms of epidermolysis bullosa (EB), a group of skin fragility disorders with profound implications for physical and mental health, even slight friction causes the layers of mucocutaneous membranes to slide apart and results in painful wounds that can resemble severe burns.
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