Preclinical studies towards application of siRNA therapy in epidermolysis bullosa simplex. (McLean-Heagerty)

Short 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.