Exploring Alternative iPS Cell Therapies for Recessive Dystrophic Epidermolysis Bullosa

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Project Summary No effective treatments are available for epidermolysis bullosa (EB), a group of rare inherited skin blistering disorders that can be devastating, and in some cases lethal. The ability to reprogram adult skin cells into induced pluripotent stem cells (iPSC) now offers the possibility of developing a permanent corrective therapy for EB. Our advances in developing safer and more efficient reprogramming, gene editing and iPSC differentiation protocols allowed us to establish the “EB iPS Cell Consortium” comprised of the University of Colorado (Drs. Roop, Bilousova, Kogut and Bruckner), Stanford University (led by Dr. Oro) and Columbia University (led by Dr. Christiano). The Consortium is currently developing an iPSC-based therapy for the severe recessive dystrophic form of EB (RDEB) that is comprised of gene-corrected epidermal sheets and composite skin grafts. The current application will explore two novel iPSC therapies for RDEB, and the non- profit foundations that currently sponsor the Consortium, the EB Research Partnership, the EB Medical Research Foundation and the Cure EB Charity, have agreed to provide the required 1 to 1 matching funds for this RFA submission. Although skin grafts may be the fastest path forward to demonstrate safety and efficacy of an iPSC-based therapy for RDEB patients, the time required to generate these grafts from genetically corrected iPSCs is lengthy and consequently expensive. Therefore, we are proposing to evaluate a “spray-on- skin” delivery system developed by Avita Medical, for delivering skin cells differentiated from gene-edited RDEB iPSCs as a more straightforward alternative to skin grafts. If successful, the “spray-on-skin” delivery system would decrease the time to patient application vs. the time and cost it takes to grow epidermal and composite grafts and would potentially produce superior outcomes for EB patients due to the lower risk of inflammation and scarring. In addition, while gene-corrected iPSC-derived keratinocytes may correct the cutaneous phenotype in RDEB patients, these cells will not be effective in treating the severe gastrointestinal manifestations associated with RDEB, which often require the use of feeding tubes. Therefore, we will also assess if the systemic delivery of gene-corrected-iPSC-derived mesenchymal stem cells (MSCs) can facilitate wound healing in both internal epithelia and the skin. If effective, the systemic delivery of MSCs would not only revolutionize how we treat EB patients, but also potentially represent a novel approach to treat many systemic multifocal diseases and injuries that affect internal organs and tissues. The following aims are proposed: Aim 1 will generate gene-corrected iPSC-derived fibroblasts and MSCs under cGMP-compliant conditions. Aim 2 will explore the feasibility of using the “spray on skin” device to deliver gene-corrected iPSC-derived keratinocytes and fibroblasts. Aim 3 will assess the ability of systemically delivered MSCs to improve wound healing in the skin and internal epithelia. Aim 4 will generate preliminary safety and efficacy data for the FDA.