519 Phase I/IIa clinical trial for recessive dystrophic epidermolysis bullosa using genetically corrected autologous keratinocytes

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is an inherited genetic skin disorder caused by mutations in the COL7A1 gene encoding type VII collagen (C7). We report the results of the ongoing Phase I/IIa clinical trial of ex vivo gene therapy for the treatment of severe RDEB. 6 adult subjects (mean age 26) enrolled in this trial carried various heterozygous COL7A1 mutations resulting in expression of only truncated C7 protein and displayed absent, or sparse rudimentary anchoring fibrils (AF) by EM. Autologous RDEB keratinocytes isolated from skin biopsies were transduced with GMP grade retrovirus carrying full-length COL7A1. 6 ∼35cm² autologous epidermal sheets were grafted onto chronic wounds that were unhealed for a mean of 8.5 years. The primary endpoint is to evaluate wound healing compared to untreated wound. Secondary endpoints included expression of C7 and restoration of AF at 3 and 6 months. No serious adverse events were reported, and no replication competent virus detected for up to 3 years. At 3 months, 94% (27/36 grafts), at 6 months, 67% (16/24 grafts) and at 12 months 50% (12/24 grafts) showed significant wound healing defined as > 75% healing compared with baseline. C7 expression and morphologically normal NC2 reactive AF were demonstrated at the BMZ of graft biopsies for up to 2 years however expression gradually diminished over time. These data demonstrate that COL7A1 ex-vivo gene transfer has a favorable safety profile and wound healing efficacy thus highlighting the potential of cell based therapy in RDEB patients.