Study of the Safety, Tolerability, and Efficacy of an iPS Cell-based Therapy for Recessive Dystrophic Epidermolysis Bullosa Delivered with a Spray on Skin Device

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Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disorder characterized by fragility of the skin and mucous membranes. Affected individuals are born with open wounds and blisters which become recurrent and/or chronic over time. Both the skin and mucosal epithelia heal with scarring, causing fusion of the fingers and toes (pseudosyndactyly) and joint contractures, microstomia, and esophageal strictures. Non-skin complications include failure to thrive, anemia, and osteopenia/osteoporosis. The course of RDEB is unremitting, and patients surviving into adulthood have a high risk of developing aggressive squamous cell carcinomas that can be fatal. Shortened life-expectancy is the norm for patients with RDEB. There is no approved disease-modifying treatment for RDEB. Current therapies are palliative and focus on promoting wound healing, nutritional support, and treating complications as early as possible. RDEB is caused by mutations in COL7A1, leading to absence or deficiency of functional collagen VII (Col7), an integral component in the adhesion of epithelia to dermis in the skin and mucous membranes. Remission from the open wounds of RDEB could be obtained if functional Col7 is replaced in the skin. However, a durable remission can only be attained if an affected patient’s cells are genetically corrected, and a sufficient number of renewable cells engraft back into wounds. This pilot, phase 1 study will evaluate the safety and efficacy of one such approach in patients with RDEB who have the common mutation c.7485+5G>A. Using an ex vivo approach, the patient’s skin cells will be genetically corrected and reprogrammed into induced pluripotent stem cells (iPSCs) in an efficient one step process. The iPSCs will be differentiated into functional keratinocytes and fibroblasts expressing Col7. These keratinocytes and fibroblasts will be transplanted to the patient using a novel Spray-on-Skin device developed by AVITA Medical. The primary objective of this study is to evaluate the safety of this treatment approach. After treatment, patients will be monitored for 1 year for the development of squamous cell carcinoma or teratomas within the treated areas, immune reactions, and other adverse events. The secondary objectives are to provide proof-of- concept data that the use of genetically corrected iPSC-derived keratinocytes and fibroblasts will function normally and are an effective treatment for chronic wounds in patients with RDEB. The expression of Col7 and formation of anchoring fibrils after treatment will be evaluated. In addition, wound closure and the durability of wound closure compared to standard wound care will be studied. We hypothesize that this treatment will be safe and well-tolerated and lead to the regeneration of histologically normal skin expressing Col7 that is not prone to re-wounding. If successful, this work will lay the foundation for the development of iPSC-based therapies for other monogenic diseases affecting internal organs, where the difficulty in monitoring adverse effects of an iPSC-based therapy would make them unlikely first targets.