) Epidermolysis bullosa (EB) is a group of inherited genetic blistering skin disorders. A severe EB subtype caused by mutations within the type VII collagen gene (COL7A1), recessive dystrophic epidermolysis bullosa (RDEB), is an autosomal recessive, inherited skin disease. People with this disease have defective or lack normal type VII collagen, which facilitates adhesion of the epidermis, or outer layer of the skin, to the inner dermal layers of the skin. The disease is characterized by painful blisters and wounds on skin and mucous membranes. The sequelae of blisters and wounds are often debilitating, disfiguring, and sometimes fatal. RDEB patients have a reduced life expectancy with early death resulting from infection, organ failure or squamous cell carcinoma (SCC). RDEB is acknowledged as an orphan and pediatric rare disease by the U.S. Food and Drug Administration (FDA). Current therapy for RDEB is limited to palliative wound care as there are currently no curative treatments and no approved drugs for RDEB. Fibrocell Technologies, Inc. (Fibrocell) is developing FCX-007, a gene-modified ex-vivo autologous fibroblast therapy that will deliver type VII collagen to the skin of RDEB subjects. Fibrocell has an open Investigational New Drug Application (IND 016582) for FCX-007. In this grant application, Fibrocell proposes to continue its interventional, open-label Phase 1/2 study to evaluate the safety, efficacy and duration of effect of FCX-007. The target indication for FCX-007 is the treatment of skin-blistering lesions in patients with RDEB confirmed by genetic testing. Reducing wound size and facilitating wound closure will be clinically meaningful by preventing or decreasing the rate of infection, pain, scarring, deformity or squamous cell carcinoma. Fibrocell expects FCX-007 to be clinically safe given the autologous nature of the therapy, and based on preclinical long-term toxicity and tumorigenicity data in animals. Clinical safety will be assessed by testing for presence of replication-competent lentivirus (RCL), type VII collagen autoantibody analysis for immune reactions to type VII collagen as well as physical examinations. Efficacy and durability of FCX-007 will be assessed by presence/increase in type VII collagen protein correctly localized to the basement membrane zone and incorporated into ultra-structurally normal anchoring fibrils. FCX-007 has been granted orphan designation, pediatric rare disease designation and fast track designation by the FDA for the treatment of subjects with RDEB. This grant will be used to assist in completing the Phase 1/2 clinical trial which may lead to a potentially effective cell-based gene therapy for RDEB subjects. Fibrocell expects to work closely with the FDA in designing the Phase 3 clinical trial while data from the current Phase 1/2 trial is being gathered. This grant proposal fulfills the goal of FDA?s Orphan Product Division grant program to support the clinical development of products for use in rare diseases where no current therapy exists.
(Public Health Relevance Statement) This application proposes to develop a cell-based gene therapy for a severe genetic skin disease called recessive epidermolysis bullosa (RDEB). RDEB represents a significant cost measured by patient suffering and economic burden to patients and their families. Despite advances in wound care and pain management, 72% of RDEB patients die before the age of 30. Fibrocell plans to genetically correct the affected person?s own skin cells and inject them back into their own skin. Effective cell-based gene therapy in this skin disease will assist in development of cell-based gene therapy for other genetic diseases.
