Grant: Project Grant

Monogenic skin diseases such as autosomal recessive congenital ichthyosis (ARCI) are caused by mutations in a single gene. If these mutations could be corrected, the disease should be mitigated. Indeed, for recessively inherited conditions such as ARCI, correction in even a small percentage of disease affected cells should be therapeutic. Recent advances, particularly the rise of CRISPR/Cas9 technology, have greatly improved the efficacy, fidelity and cost of gene editing. The overall goal of this project is to evaluate the feasibility of topically applied CRISPR/Cas9 mediated strategy to correct monogenic mutations in human skin. Whilst the components of the CRISPR/Cas9 system are not themselves capable of overcoming the skin barrier, a major focus will be to develop and evaluate smart delivery strategies for these biomacromolecules. Firstly, the ability of different delivery systems such as nanocarriers for gene-delivery, microneedles and skin-penetrating peptides to deliver CRISPR/Cas9 systems into human skin will be explored. In parallel, CRISPR/Cas9 based gene editing strategies will be developed and optimised in keratinocytes - the primary cell type of the epidermis of the skin - derived from healthy subjects and ARCI patients. Once strategies capable of correcting ARCI causing mutations have been established, the proportion of gene correction in the epidermis required to produce therapeutic effects will be determined. The overall intent of this project is to demonstrate the feasibility of CRISPR/Cas9 mediated gene editing for the treatment of monogenic diseases, and to lay the ground work for future optimisations to improve on its therapeutic potential.