Our research Completed projects McLean/Heagerty 1 (2014) To be in a position to move to clinical trials of siRNA on EB Simplex Contents: Project information Lay summary Preclinical studies towards application of siRNA therapy in Epidermolysis Bullosa Simplex Investigator: Professor W. H. Irwin McLean, Professor of Human Genetics and Head of Division of Molecular Medicine Co-applicant: Dr Adrian H.M. Heagerty Institution: Division of Molecular Medicine, Epithelial Genetics Group; Medical Sciences Institute, University of Dundee Grant: £192,804.00 (01/11/2011 – 31/10/2014) Lay summary Epidermolysis bullosa simplex (EBS), the commonest form of EB, is associated with skin blistering which causes pain and discomfort that negatively impacts quality of life. There is a weakness in important structural proteins (keratins) in the outer layer of skin, which means that the cells are unable to resist even minor stress and so they rupture and fluid accumulates resulting in painful blisters. The weakness is caused by mutations, or “spelling mistakes”, in genes that control manufacture of two keratins: K5 or K14. Genes are inherited in pairs – one from the father and one from the mother. Although EBS patients have one ‘good’ gene they also have one mutated gene that overtakes the functioning of both genes to produce the weak keratin molecules. If the mutated gene can be ‘switched off’, without affecting the good copy of the gene, then the good gene can function properly to produce normal keratin. This research group previously identified families with an unusual recessive form of EBS. In these families, there are some people with only one active copy of a keratin gene and these individuals have perfectly normal skin. This proves that the approach of switching off the ‘bad’ keratin gene would cure EBS. The information from genes that tell a cell to manufacture proteins (in this case keratin) is sent by messenger molecules called RNA; the RNA will transmit messages from both good genes and mutated genes. There is now new powerful technology called ‘short interfering’ RNA (siRNA) which are agents that can alter the RNA and change the ‘manufacturing instructions’. Funded by a previous DEBRA grant, this group have found siRNAs that can prevent the manufacture of weak K5 and K14 without affecting the normal gene function, so when skin cells are treated with these agents they can produce normal keratins One issue in developing an effective drug is finding the best way to deliver it to where it is needed. siRNA is a bit bigger than most drugs so needs special delivery mechanisms. Recently a ‘gene cream’ has been developed that is capable of taking these kinds of agents across the skin and into the keratin-producing cells. This group have used their original siRNA and also produced a modified form that crosses cell membranes more easily. Both of these have been shown to successfully silence the mutant genes when incorporated into the cream. Together, these studies pave the way for larger clinical trials of siRNAs to develop treatments for EBS. Investigator biography Irwin McLean PhD DSc FRS FRSE FMedSci is Professor of Human Genetics and Scientific Director of the Centre for Dermatology and Genetic Medicine at The University of Dundee. His research group has identified the causative genes for more than 20 human diseases, which include a number of disorders of keratins and associated structural proteins. More recently, his laboratory identified defects in the filaggrin gene (a gene that codes a protein that helps to bind structures in the skin). Filaggrin gene defects have been found to be the cause of the common dry skin condition called Ichthyosis vulgaris and also showed that these same mutations, carried by more than 10% of various human populations, are the major genetic predisposing factor for atopic eczema and associated allergic conditions, including allergic forms of asthma. This work won several international awards. In recent years the main focus of his work has been therapy development for skin disorders with research programmes in RNA-interference and small molecule therapy development aimed at inherited disorders of the epidermis, as well as atopic eczema and asthma. Irwin has published more than 250 scientific papers and holds a number of patents. He is a Fellow of The Royal Society,The Royal Society of Edinburgh and the Academy of Medical Sciences. Irwin sits on the editorial boards of dermatology journals as well as the advisory boards of a number of skin disease patient organisations.