| ABSTRACT OF
RESEARCH
Epidermolysis Bullosa simplex
(EBS) is a dominant genetic condition. It is mainly caused by mutations (genetic spelling
mistakes) in either one of two genes which are the recipes for making proteins known as
keratins K5 and K14. About 40% of people with the most severe form of EBS, the
Dowling-Meara type, carry a mutation known as R125C in the K14 gene. Abnormal K14 protein
is made by the mutated gene and this unfortunately is able to bind to and prevent the
normal K14 present from doing its job, leading to skin blistering.
In a very small number of families affected by a recessive type of EBS, there are some
completely normal individuals who have only one active copy of the K14 gene, as the other
copy has been “knocked out” by a special type of mutation. Thus we know that
only one copy of the K14 gene is enough to make normal skin and, if we had a means of
switching off the defective gene in EBS, the normal gene could do its job and the skin
would no longer blister.
The Dundee groups have developed two systems that have the potential to carry this out.
One of these is an artificial gene, called a ribozyme gene, which can switch off the K14
gene carrying the very common R125C mutation, but which has no effect on the normal K14
gene. The second method, based on very new technology RNA interference (RNAi) involves
switching off both the normal and abnormal K14 genes and replacing them with a modified
K14 gene that does exactly the same job in the cell as the normal K14 gene. This second
method has the potential to treat all EBS patients regardless of what their individual
mutations in the K14 gene happen to be. It can also be adapted to treat patients carrying
the K5 mutations and even patients with mutations in other keratin genes (19 of which are
now linked to human disorders).
This programme grant is designed to test both these models very thoroughly in cultured
skin cells from EBS patients, then test both systems in a mouse model of EBS and develop
methods to deliver either system into the human skin. Ultimately, the aim is to carry out
a small-scale clinical trial on EBS patients with whichever system proves to be the safest
and most effective following animal and cell-based testing.
FINANCIAL
SUMMARY
|
Year 1
£ |
Year 2
£ |
Year 3
£ |
Year 4
£ |
Year 5
£ |
|
|
|
|
|
|
| Staff |
116,643 |
120,442 |
124,090 |
127,392 |
129,405 |
| Expenses |
79,200 |
88,200 |
92,610 |
97,240 |
102,103 |
| Equipment |
43,000 |
0 |
0 |
0 |
0 |
| Management @5% |
13,070 |
10,430 |
10,835 |
11,230 |
11,575 |
|
|
|
|
|
|
| TOTAL |
274,450 |
219,072 |
227,535 |
235,863 |
243,082 |
The
programme will be reviewed by DebRA’s scientific advisors after 24 months to confirm
that suitable mouse models are available. |
