In vivo model systems to develop filaggrin as a drug target in atopic disease

We recently discovered the major gene that causes eczema and a host of other conditions associated with eczema, such as allergies and eczema-associated asthma. The filaggrin gene, which makes a protein essential for skin barrier formation, is completely deactivated by genetic mutations in about 10% of the population, leading to ?leaky? skin that allows foreign material such as bacteria, allergens and chemicals to enter the body. These foreign substances are seen by the immune system and this leads to inflammation of the skin (eczema) and as a secondary event, other systems such as the lungs (asthma). The filaggrin gene is an ideal target for two different types of drugs that can eithr rescue certain defective genes and switch them back on again, or boost the activity of a gene. We have shown that these drugs can indeed rescue or boost filaggrin production in cells and skin. This grant is designed to develop animal models that closely mimic the human filaggrin defects. This will allow us to dissect out the disease mechanisms and importantly, to test the new therapy systems aimed at this gene. This project has the potential to treat over 4 million people in the UK, or 10s of millions worldwide. If administered early, such drugs could prevent the onset of eczema and associated diseases, such as allergies and certain types of asthma and hay fever.

We recently discovered that loss-of-function mutations in the filaggrin gene cause atopic dermatitis (eczema) and a host of other associated atopic conditions, such as allergies and eczema-associated asthma. Filaggrin is essential for skin barrier formation and is deactivated by genetic mutations in about 10% of the population, leading to permeable skin that allows antigens, allergens and chemicals to enter the body, leading to inflammation of the skin (eczema) and other organ systems (allergies and asthma). The filaggrin gene is the best target yet discovered for drugs such as gentamicin, negamycin and others that can rescue premature termination codon (nonsense) mutations by binding to the 16S ribosome subunit and allowing the ribosome to read-through the mutant stop codon. We have shown that this class of drug an indeed rescue filaggrin production in cultured cells and skin from filaggrin-null patients. A medicinal chemistry component, in house at nearby St Andrews University, is aimed at developing one new type of low toxicity, highly efficacious readthrough compound, negamycin, for testing in cell culture and animal models of filaggrin-null atopy. We have also shown that another class of small molecules, PPAR-gamma agonists, many of which there are known, are able to increase expression of the filaggrin gene in cultured cells. Since most individuals with filaggrin-related atopy are heterozygous carriers of null-mutations, these drugs might be used to boost expression of the normal allele to therapeutic effect. Mouse models of increasing complexity and similarity to the human disease will be developed for testing both read-through and filaggrin-boosting drugs in vivo using both reporter gene and humanized phenotypic readouts. This project has the potential to find new drugs aimed at treating about 4 million people in the UK, or several 10s of millions worldwide. If administered early, such drugs could prevent the onset of eczema and atopic diseases.