Next generation genome editing for Recessive Dystrophic Epidermolysis Bullosa
Lay summary
This project uses ‘molecular scissors’ to target and remove sections of the faulty gene for collagen VII which causes the skin fragility in Recessive Dystrophic Epidermolysis Bullosa (RDEB). This region is then repaired using a ‘patch’ with the correct DNA code.
The first aim of the project is to generate a set of ‘molecular scissors’ to correct the majority of the collagen VII mutations that cause RDEB. The second aim is to increase the body’s response to collagen VII, to help make up for the fact that people with RDEB have less of it than non-sufferers.
Scientific Summary
Gene correction of RDEB has been successfully done by gene addition and gene editing. With on/off-target profiles largely known, methods are being scaled up using GMP-level SOPs for clinical testing.
Correction of single COL7A1 mutations is unlikely to have the commercial and clinical impact we seek. Therefore, we will focus on two advanced gene-editing technologies: regional correction of COL7A1 and up-regulation of COL7A1 beyond physiological levels. We will assesstheir translational fitness and commercial robustness by developing gene editing reagents at GLP/GMP grade and by live testing in human-murine xenotransplanted 3D grafts.
We propose therefore, to correct both the primary lesion in COL7A1 and the suboptimal COL7A1 expression. With advanced versions of current genetic/cellular technologies already developed, we expect to generate a clinical product within five years. This personalized therapy to correct RDEB-modifying genes offers the hope of curing RDEB.
Related Publications
Thompson, E.L., et al. Genes and compounds that increase type VII collagen expression as potential treatments for dystrophic epidermolysis bullosa Exper Dermatol. 2022;00:1-11
Osborn, M.J., et al. Base Editor Correction of COL7A1 in Recessive Dystrophic Epidermolysis Bullosa Patient-Derived Fibroblasts and iPSCs J Invest. Dermatol. 2020;40,338-347
Osborn, M.J., et al. CRISPR/Cas9-Based Cellular Engineering for Targeted Gene Overexpression Int. J. Mol. Sci. 2018;19(4),946
Webber, B.R., et al. CRISPR/Cas9-based genetic correction for recessive dystrophic epidermolysis bullosa. npj Regen. Med. 2016;1,16014
