A Stem Cell-Based Therapy for Recessive Dystrophic Epidermolysis Bullosa Delivered with a Spray-On Skin Device
Abstract
Current therapy for patients with epidermolysis bullosa (EB), a group of rare inherited skin blistering diseases, is primarily limited to wound care. EB is caused by genetic mutations in structural proteins of the skin and sentences those afflicted to a life of severe pain and disability due to constant blistering and scaring, and in some cases, early death. This is especially true for severe autosomal recessive dystrophic EB (RDEB), which is caused by mutations in the COL7A1 gene, encoding for the production of Type VII Collagen (Col7), a structural protein that anchors the outer layer of the skin, the epidermis, to the dermis. The technological breakthrough that allows adult skin cells to be reprogrammed into immature induced pluripotent stem cells (iPSCs) now offers the possibility of developing a permanent corrective therapy for RDEB without the risk of immune rejection. Specifically, skin cells can be biopsied from a patient suffering from RDEB and then reprogrammed into iPSCs. The iPSCs can then be grown outside the body, genetically corrected, differentiated into new skin stem cells, and then administered back to the same patient as an autograft. The main hypothesis of this proposal is that epidermal cells and dermal cells derived from gene corrected RDEB iPSCs when grafted onto wounds will adhere tightly and provide long-term wound closure. The objective of this new research effort is to continue to develop and improve our iPSC-based therapy for RDEB as proposed in our in our original application. There are two major changes proposed in our current application. We originally proposed to differentiate genetically corrected RDEB iPSCs into epidermal (keratinocytes) and dermal (fibroblasts) cells using a standard protocol where iPSCs are grown in culture as a single layer (in one dimension). However, cells derived by this method failed to form stable human skin when grafted onto mice. We recently discovered that the differentiation of genetically corrected RDEB iPSCs under conditions that allow growth in three dimensions results in the formation of skin organoids (miniature pieces of human skin). Furthermore, epidermal and dermal cells isolated from skin organoids consistently form stable skin when grafted onto mice. Thus, our new application proposes to use skin cells isolated from human skin organoids. Our previous award, proposed to deliver epidermal and dermal cells derived from genetically corrected RDEB iPSCs to RDEB patients as composite skin grafts, comprised of epidermal and dermal cells. However, the time required to generate composite skin grafts is lengthy and consequently expensive due to the long period of use of a current Good Manufacturing Practice (cGMP) manufacturing facility. Therefore, our new application is proposing to deliver genetically corrected iPSC-derived skin cells using a spray-on-skin delivery system developed by AVITA Medical that is currently approved by the U.S. Food and Drug Administration (FDA) for treating severe burns. The use of the spray-on-skin delivery system will not only decrease the time to patient application, but also greatly reduce the cost compared to growing composite skin grafts. It may also produce superior outcomes for RDEB patients due to the lower risk of inflammation and scarring. A major goal of our current application is to adapt the production of organoid-derived keratinocytes and fibroblasts to manufacturing conditions required by the FDA and to generate a set of safety and efficacy data to fulfill regulatory requirements for FDA approval of a clinical trial for RDEB. Therefore, this application addresses Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Portfolio Category: Internal Medicine and the FY22 PRMRP Topic Area: Epidermolysis Bullosa. The FY22 PRMRP Strategic Goal is Treatment: to develop and test therapeutics or dressings that enhance wound healing. iPSC-based strategies similar to the one proposed in this application, whe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310303
Entities
People
- Dennis Roop
Organizations
- United States Army
- University of Colorado Denver