Evaluation of long-term effect on skin homeostasis and regeneration in a RDEB mouse model using different delivery methods of LNPs encapsulating mRNA-based base editing approach.
Lay summary
Over the last 30 years, we have learned that all forms of DEB result from faults (mutations) in the type VII collagen gene (COL7A1). These mutations alter the type VII collagen protein (C7) in the skin which normally makes adhesion structures called anchoring fibrils that hold the outer layer (epidermis) and inner layer (dermis) together to prevent blistering. Our research looks at a different approach to gene therapy, developing a technique called “gene editing”.
This method allows us to try to correct the COL7A1 mutations in a more focused manner, somewhat like fixing typos in a word document by cutting and pasting correct text directly over the error. Our research work therefore looks to develop gene editing for COL7A1 mutations as future new therapies for DEB. Our previous work involved testing penetration of gene editing using chemical bubbles called “lipid nanoparticles” through 3D human skin equivalents. However, we also need to test delivery of this system in a DEB animal model to assess the long-term benefit of our treatment for skin health and wound healing. Importantly, this is considered an essential pre-requisite to support clinical translation of the project, for which we will seek further funding once our animal work is completed.
Scientific Summary
This project focuses on in vivo testing of gene editing using lipid nanoparticles. After highly efficient correction of a COL7A1 pathogenic variant in RDEB patient fibroblasts using lipid nanoparticles, we will target the equivalent single nucleotide variant in a recently published DEB disease model (Smith et al., 2021). We will test different delivery routes of lipid nanoparticles, in vivo targeting efficiency of epidermal and dermal cells, and the long-term therapeutic implications for skin homeostasis and repair. These essential preclinical data will enable us to develop the clinical translation of our novel gene therapy approach.