Our research Completed projects Hickerson 2 (2019) Investigating the use of Ultrasound as a Delivery Mechanism for an Epidermolysis Bullosa Simplex Therapy Contents: Project information Lay summary Project Title: Delivery of antisense oligonucleotides to the basal layer using ultrasound Investigators: Dr. Robyn Hickerson, Dr. Michael Conneely and Professor Irwin McLean Institution: Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee Start Date: Q3 2018 End Date: Q2 2019 Duration: 1 year Grant amount: £8,500 Lay Summary Epidermolysis bullosa simplex (EBS) is caused by faults in KRT5 and KRT14; two genes that code for the proteins keratins 5 and 14, which are key to the integrity of the skin structure. Everybody carries two copies of these genes, one inherited from their mother, the other from their father. A mutation or fault in the DNA in only one of the two copies is sufficient to cause EBS. The production of protein in the skin surface, for example keratin 14 from the KRT14 gene, is mediated by a molecule called the KRT14 messenger RNA and this project looks at targeting this messenger to stop the wrong protein from being made. Molecules called antisense oligonucleotides (ASOs) can be designed to bind to and promote the destruction of specific messenger RNAs. These are designer synthetic molecules. Because of the way they work, they may provide a therapy that can stop the disease process of EBS, by preventing the messenger from making the wrong kind of protein. In Dundee, the team are pursuing an approach that uses ASOs to stop faulty KRT14 messenger RNA Together with WAVE Lifesciences (a pharmaceutical company in Boston, USA), the team have been able to identify several ASOs that can specifically destroy the faulty KRT14 messenger RNA in human skin cells grown in the laboratory. They have also treated human skin (waste skin after surgery) with these ASOs; however, they have not been as successful in the skin model so far most likely due to the difficulty involved in penetrating the skin’s outer protective layer. The team propose to use certain ultrasound frequencies (and combinations of frequencies) to deliver ASOs to the region of the skin that produce KRT14 messenger RNA to investigate this as a delivery mechanism in their skin model. The hope is that this approach will take the research one step further towards developing an ASO therapy and possibly towards understanding skin biology in EBS. Investigator Biographies Dr. Robyn Hickerson Robyn Hickerson’s primary research focuses on drug discovery for rare genetic skin disorders. A major arm of this program is focused on nucleic acid-based therapeutics – specifically the development of strategies to deliver these potential therapeutics. Her team has developed novel and state-of-the-art ex vivo human skin models required for evaluation of delivery and efficacy. With programmes primarily focused on antisense therapeutics through a partnership with WAVE Life Sciences, the primary goal is to bring these molecules to the clinic within the next few years. In addition to nucleic acid-based therapeutics, Dr. Hickerson is also interested in developing small molecules to treat genetic skin disease. To this end, her team is engaged in three collaborative projects with the Drug Discovery Unit and the National Phenotypic Screening Centre, both within the University. Professor Irwin McLean Irwin McLean is Professor of Human Genetics at The University of Dundee. His research group has identified the causative genes for more than 20 human diseases, including a number of diseases of keratins and associated epithelial structural proteins. In particular, he has a long-standing interest in the genetics of skin fragility disorders such as epidermolysis bullosa simplex (EBS) and development of therapy for this and closely related keratin disorders. In recognition of his research, Irwin has won or been awarded multiple prestigious global awards and prizes. He lectures across the world and was awarded the Royal Society’s Buchannan Medal for distinguished contributions to medical sciences in 2015. In 2015, Irwin’s laboratory relocated to the Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, due to his close interactions with the Drug Discovery Unit in developing therapy for skin disease. Irwin also has close links with the National Health Service and holds Honorary NHS Consultant Clinical Scientist positions in both Human Genetics and in Dermatology. He has been elected as a Fellow of the Royal Society of Edinburgh (2005), a Fellow of the Academy of Medical Sciences (2009) and a Fellow of the Royal Society (2014). Irwin works very closely with patient advocacy organisations DEBRA, PC Project and others to deliver patient support, molecular diagnosis and registries of genetically-defined subjects to enable clinical trials of new genetic medicines. Dr. Michael Conneely Michael Conneely obtained his PhD in Physics from the University of Dundee where he focussed on the application of ultrasound for the delivery of therapeutics throughout the body. For the past three years he has worked as part of the Hickerson team developing state-of-the-art ex vivo skin models for use in the evaluation of delivery and efficacy of therapeutic compounds. The most recent aspect of this work involves a collaboration with the National Phenotypic Screening Centre, a world-class facility utilising the latest in robotic and automated platforms, to design a multi-well skin culture system for use in high-content screening (HCS) applications. Dr Conneely is also engaged in several other activities including: adapting novel histology techniques for use with skin tissue, enabling new ways of investigating skin structure and responses to stimuli; and working towards improving patient comfort in their day-to-day lives by coordinating a collaboration with colleagues in Physics and Engineering looking at the feasibility and design of cooled footwear.