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DEBRA Funds 4th year towards Novel Gene Technology for Epidermolysis Bullosa

DEBRA Funds 4th year towards Novel Gene Technology for Epidermolysis Bullosa

We are pleased to announce funding for a fourth year of the University of Dundee’s research into novel gene technology for treating Epidermolysis Bullosa has been agreed.

A further £153,550 towards a total of £504,472 has been provided to enable the team lead by DEBRA Clinical Fellow, Dr Peter van den Akker, to develop two types of gene technology that can target genetic mutations caused by EB.

About 70% of EB cases are classified as EB Simplex (EBS), which is caused by mutations in the genes that manufacture proteins called keratin 5 and keratin 14 (KRT5 and KRT14). Keratins are vital to ensure a strong and healthy skin.

There are no effective treatments for EBS, which is characterised by persistent blistering and poor healing of the skin both internally and externally. Genes are inherited, one copy from each parent. Only one copy of the gene needs to contain a mutation to cause EBS – these are called dominant genes. By selectively suppressing the expression of the faulty copy of the gene, this allows the normal copy of the gene to work properly, a strategy that is believed could be developed into an appropriate therapy for EBS.

When the genetic or DNA sequence of a gene is read, akin to a recipe, it is eventually translated through an intermediate stage (messenger RNA) into the production of protein – in this case, the keratins found in the top layer of the skin, the epidermis.  New developments in gene technology mean that it is now possible to make a small piece of nucleic acid that will bind to the messenger RNA and inactivate it. This is called gene silencing technology. Antisense oligonucleotides (ASOs) are small pieces of nucleic acid that can be designed to specifically bind to messenger RNA copies of a certain gene in order to destroy these.

Dr van den Akker and his team have been developing methods to use this new gene silencing technology to the point where EBS-specific therapeutics could be taken into the clinic. They have been working with the pharmaceutical company WAVE Life Sciences on this project and have identified several ASOs that can silence the KRT14 messenger RNA in human skin cells grown in the laboratory.

Using ASOs for Recessive Dystrophic Epidermolysis Bullosa (a more severe form of EB) is equally challenging. Recessive dystrophic epidermolysis bullosa (RDEB) is caused by faults in the COL7A1 gene, the genetic recipe for the protein collagen type 7. Everybody carries two COL7A1 copies, but, in contrast to EBS, there needs to be a mutation on both copies of the gene to exhibit the symptoms of RDEB – these are recessive genes. The approach to destroy the faulty messenger RNA will not work here. However, a different class of ASOs can be used which can trick the cells into removing the part of the messenger RNA where the mutation is located. This approach is called ‘exon skipping’ and although this will lead to a slightly shorter messenger RNA, it can still be used to produce active (but shorter) type 7 collagen.

The aim is also to study whether the functional ASOs can induce exon skipping of the COL7A1 gene and silencing of the mutant KRT14 RNA copy when applied to human skin (using leftover skin from surgical procedures). This involves studying ways to deliver these ASOs to the right location in the skin. Therefore, the Fellow is working closely with Dr Robyn Hickerson and her team.

“We’re delighted to support this research for a further year. With an estimated 70% of those living with EB having Simplex this project is trying to develop a treatment for these patients. However, such vital work will hopefully lead to further development of this type of therapy, and DEBRA UK aims to find a cure for all types of EB." - Jim Irvine, Acting Chairman, DEBRA Board of Trustees


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