Splicing therapies for Dystrophic Epidermolysis Bullosa (SpliceEB)

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare devastating skin disease without current effective treatment. The clinical management of this genetic disease is mainly supportive with symptomatic treatment. Gene therapy represents a compelling strategy for RDEB. However, critical shortcomings associated to peculiarities of the therapeutic gene (COL7A1) could compromise the use of standard ex vivo gene transfer strategy shown to be successful in a patient with the junctional form of Epidermolysis Bullosa reported by Mavilio and co-workers. This project thus aims at developing a novel, safer, efficacious and long-lasting ex vivo gene therapy approach. In this study we will test the 3` trans-splicing correction approach for the COL7A1 pre-mRNA on keratinocytes from patients carrying in homozygosis the c.6527dupC mutation in exon 80, which is highly recurrent in RDEB patients in Southern Europe. Gene correction will be assessed in vitro and in vivo. We will pay great attention to safety issues at the molecular level (e.g. transgene-host genome interactions) as well as to sustained regeneration of gene- corrected skin using a robust skin-humanized mouse model. Another part of the proposal suggests to develop a COL7A1 humanized RDEB mouse model suitable for testing our 5` and 3` trans-splicing therapies. In this grant application we also aim to validate the 5` trans-splicing approach for the correction of mutations in the murine Col7a1 gene using a suitable hypomorphic EB mouse model. The SpliceEB consortium is formed by young scientists in the Skin Gene Therapy field from The Netherlands (Dr. M. Pasmooij, University Medical Center Groningen; coordinator), Germany (Dr. A. Nyström, University Medical Center Freiburg), Austria (Dr. E. Murauer, Univ. Hospital Salzburg, EB House) and an expert in the development of Antisense-mediated exon (AON) skipping for genetic diseases from The Neterhlands (Dr. A. Aartsma-Rus, Leiden University Medical Center).

No additional funding sources recorded.