Ribozyme Gene Therapy for Dominant Forms of Epidermolysis Bullosa

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Ribozyme Gene Therapy for Dominant Forms of Epidermolysis Bullosa

Name of Researchers:		Dr W H Irwin McLean

Places of Research:		University of Dundee

Approved by DebRA Medical & Scientific Advisory Panel:		4 December 2000

Budget approved by DebRA central Committee:		27 January 2001

Date Commenced:		extended by 1 year to 3 years

SUMMARY OF RESEARCH BEING UNDERTAKEN

Epidermolysis Bullosa is a set of genetically inherited conditions affecting 1 in 17,000 of the population. A fault in a gene causes the skin to be extremely fragile. The layers of the skin do not adhere properly and painful widespread blisters occur very easily. These can lead to increasing disfigurement, disability and in the most severe forms death in early childhood.

Summary of Research

EB Simplex is caused by defects in keratin genes. Keratins are filamentous proteins which are found in a number of tissues including the skin. They are important for its structural integrity and alterations in these proteins can make the cells fragile and less resilient to mechanical stress. A great deal of progress has been made in recent years in identifying the mutations (changes in DNA) which are responsible for EB Simplex and in some cases it is now possible to carry out prenatal testing for the disorder. There is still no treatment or cure.

This Research Project extends an existing DebRA grant for a further year. Projects are normally approved for two years and only extended if research results are promising.

For technical reasons, gene therapy for dominant forms of EB is potentially more difficult than that for recessive forms of EB. One way in which dominant types of EB might be treated depends on finding a way of completely silencing genes.

Dr Ana Terron, a DebRA funded Research Assistant in Dr Irwin McLean’s laboratory, has developed a method for switching off expression of the human K14 gene, one of the two keratin genes involved in EB Simplex. Small molecules called ribozymes have been designed that are able to seek out and destroy the expression of the K14 gene in skin cells. This opens up the possibility of switching off K14 in cells from EB Simplex patients and replacing this with a new version of the K14 gene.

This method can be adapted for use in other dominant forms of EB involving the keratin 5 in EB Simplex or type VII collagen in Dominant Dystrophic EB. The system needs a lot of further development and testing but it is a step in the right direction towards understanding and perhaps treating the most common forms of EB.

Dr McLean is an experienced and successful EB Researcher. In 1998 he was awarded a Wellcome Programme Grant of Ł818,000 to establish a laboratory in the UK. Dr McLean is also the holder of the DebRA Princess Diana Research Fellowship.

This project will further enable the development of successful treatments and combine collaboration, which is one of the hallmarks of EB research throughout Europe.