1122 ZKN-0013 promotes premature termination codon readthrough to restore collagen VII protein expression and function in recessive dystrophic epidermolysis bullosa (RDEB)

RDEB is an autosomal recessive skin disease characterized by unremitting blistering occurring with minimal trauma and profound scarring that leads to loss of mobility severe malnutrition. caused mutations in the COL7A1 gene encoding type VII collagen (COL7). Almost 30% patients carry at least one nonsense mutation leading premature termination codons (PTCs) (deb-central.org). Currently there a large unmet need for treatment. Eloxx Pharmaceuticals developing small molecule, ZKN-0013, orally bioavailable, modified macrolide promotes readthrough PTCs thereby restoring expression full-length proteins. ZKN-0013 demonstrated dose dependent read-through 5 distinct patient derived fibroblasts keratinocytes. The activity resulted up 18-fold increase COL7 protein levels surpassing efficacy gentamicin, which had improved wound healing reduced blister formation (Woodley et al., 2017). Prolonged treatment further increased levels. Functionality restored was confirmed reversal hyper-motility phenotype fibroblasts. PTC multiple genotypes, across cells. Efficacy mediated comparable or better than therapeutic benefit patients. Our findings provide pre-clinical support evaluate potential RDEB.