SpliceEB

Severe generalized recessive dystrophic epidermolysis bullosa (RDEB-sev gen) is the most devastating form of the inherited skin disease epidermolysis bullosa. Patients suffer from life-long painful blistering and chronic wounds that significantly affect quality of life. Fusion of the fingers and toes occurs due to constant wounding of the digits. The disease is associated with increased mortality as a result of skin cancer. RDEB-sev gen is caused by genetic defects (= mutations) within the human COL7A1 gene resulting in absence of the protein type VII collagen, which is the key component of anchoring fibrils that secure attachment of the two skin layers. The clinical management of this rare disease is mainly supportive with symptomatic treatment, since currently no cure exists. We will investigate the feasibility of two causative treatment options for RDEB that are both based on modulation of gene splicing: 1) trans-splicing with human skin grafts, which aims to replace a large stretch of the faulty gene; 2) antisense oligonucleotide (AON)-mediated exon skipping for systemic administration, which skips the defective part of the gene. Both approaches aim at correction of the COL7A1 coding sequence in patients’ skin cells, resulting in the production of a functional type VII collagen protein for skin adhesion and thus amelioration of the RDEB phenotype. The planned experiments will be performed to assess feasibility, safety and efficacy in animal models towards translation to clinical trials.