Delivery of antisense oligonucleotides to the basal layer using ultrasound (Hickerson 2)Completed
|Project lead||Dr Robyn Hickerson, Dr Michael Conneely and Prof Irwin McLean|
|Organisation||School of Life Sciences, University of Dundee, Dundee, UK|
|Project budget||GBP 8,500.00|
|Start date / Duration||01. Jul 2018 / 12 months|
|Funder(s) / Co-Funder(s)||DEBRA UK|
|Research area||Molecular therapy|
Short 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 KRT14messenger 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.