Epidermolysis bullosa (EB) is a family of inherited genetic blistering skin disorders. Children lacking normal type VII collagen develop a severe, scarring EB subtype, recessive dystrophic epidermolysis bullosa (RDEB), which produces painful blisters and wounds on skin and mucous membranes. RDEB subjects have a shortened life expectancy with early death from infection, organ failure or squamous cell carcinoma (SCC). Current therapy for RDEB is limited to palliative wound care as there are no therapies available that alter the course or severity of the disease. We have focused on developing molecular therapy for RDEB. We have demonstrated that genetically corrected RDEB keratinocytes engineered to express type VII collagen can correct human RDEB skin tissue grafted onto immune deficient mice. We now plan to extend this approach to RDEB subjects by grafting genetically corrected autologous RDEB keratinocytes back into the skin of RDEB subjects in a human gene transfer clinical trial.
The Specific Aims of this application are to deliver type VII collagen to the skin of RDEB subjects and to evaluate the effectiveness and duration of the beneficial effect. This R01 application documents our previous long term success in animal models, our gene transfer technology development, and our current plan to identify and enroll subjects for a Phase 1 clinic trial. Successful gene transfer will produce type VII collagen protein correctly localized to the cutaneous BMZ that is incorporated into ultrastructurally normal anchoring fibrils. We will assess the durability of type VII collagen at the levels of genomic retention, as well as mRNA and protein expression. We will evaluate gene expression profiles of the original and the gene corrected skin. We will evaluate grafted skin for unwanted immune response to the delivered type VII collagen protein. Analysis for any humoral or cellular immune responses in RDEB recipients of genetically corrected autologous skin grafts will provide important information both about the likelihood of success of this approach as well as insight into any failure of durability. This application fulfills the mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases through focused research upon treatment of this severe skin disease by translational application of previous basic science successes. We expect that this trial may lead to a potentially effective cell based therapy for these subjects and may further support corrective gene therapy for genetic skin diseases.

Public Health Relevance

This application proposes to develop gene therapy for a severe skin disease called recessive dystrophic epidermolysis bullosa (RDEB). We plan to correct the affected person's own skin cells and transplant their own cells back onto their skin. Effective gene therapy in this skin disease will assist in development of gene therapy for other genetic diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
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Stanford University
Schools of Medicine
United States
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Gorell, Emily; Nguyen, Ngon; Lane, Alfred et al. (2014) Gene therapy for skin diseases. Cold Spring Harb Perspect Med 4:a015149
Melo, Sandra P; Lisowski, Leszek; Bashkirova, Elizaveta et al. (2014) Somatic correction of junctional epidermolysis bullosa by a highly recombinogenic AAV variant. Mol Ther 22:725-33
Sun, Bryan K; Siprashvili, Zurab; Khavari, Paul A (2014) Advances in skin grafting and treatment of cutaneous wounds. Science 346:941-5
Gorell, Emily S; Tichy, Andrea L; Lane, Alfred T (2011) Successful investigational new drug preparation without reinventing the wheel. J Invest Dermatol 131:996-8
Siprashvili, Zurab; Nguyen, Ngon T; Bezchinsky, Maria Y et al. (2010) Long-term type VII collagen restoration to human epidermolysis bullosa skin tissue. Hum Gene Ther 21:1299-310