Novel Approaches for Read-through of Nonsense Mutations in COL7A1

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 DESCRIPTION (provided by applicant): Dystrophic epidermolysis bullosa (DEB), an inherited connective tissue disease, manifests with blisters, erosions and chronic ulcers in the skin and mucosal membranes. The signs and symptoms of this condition vary widely among affected individuals; the most severe cases involve widespread blistering that can lead to scarring disfigurement and other serious medical problems. Furthermore, as a complication of the chronic skin damage, patients with DEB have an increased risk in development of highly aggressive squamous cell carcinomas. This disease is caused by mutations in the COL7A1 gene, ~10% of them being nonsense mutations. So far there is no effective treatment. The incidence of EB is estimated to be ~1:20,000 implying that there are 30,000-40,000 affected individuals in the United States. Assuming the same global incidence, there are over half a million EB patients in the world. Since approximately 20 percent of the patients have the dystrophic forms, even with ~10% of patients having nonsense mutations in COL7A1, thousands of patients would benefit from a successful strategy of PTC read-through worldwide. This study will test novel pharmaceutical compounds that facilitate read-through of nonsense mutations and counteract nonsense-mediated mRNA decay, thus allowing synthesis of the full-length polypeptide from the mutant allele, with the hypothesis that correction of COL7A1 mutations will counteract their phenotypic consequences. The read-through compounds with antagonistic properties against nonsense-mediated mRNA decay will be tested in vitro in cell cultures with mutant keratinocytes and fibroblasts derived from the skin of patients with DEB as well as in vivo using zebrafish as a platform. Preclinical demonstration of the efficacy of compounds, such as PTC124 and Amlexanox, can be translated quickly to the clinical trials due to the fact that the pharmacokinetics and toxicology profiles of these drugs have already been established.