One of the key strategic aims of the Dermatology and Genetic Medicine group is to translate our discoveries in genetics into new improved treatments for patients.  In close collaboration with the Drug Discovery Unit, we are actively pursuing a number of small molecule drug discovery projects aimed at treatment of genetic disorders, particularly those affecting the skin.  The first of these is aimed at the rare keratinizing skin disorder pachyonychia congenita (PC), which is caused by mutations in any one of the genes encoding keratins K6a, K6b, K6c, K16 or K17.  From a high-throughput screen of a small molecule library, we showed that surprisingly, the cholesterol-lowering statins show inhibitory effects on the expression of PC-related keratin genes.  This work, funded by PC Project, is now at the clinical trial stage.  Secondly, we have developed novel chemical compounds that may be able to benefit patients with certain types of genetic mutations.  Here, our main target disorder is the very severe skin blistering condition recessive dystrophic epidermolysis bullosa (RDEB).  This project, originally financed by an MRC Project grant and further MRC DPFS funding, is very well developed and in May 2011, we signed one of the first Discovery Partnerships with Academia with GlaxoSmithKline (GSK) - one of the world’s leading research-based pharmaceutical and healthcare companies (click here for Press Release).  This new GSK alliance model focuses on making a medicine, rather than supporting basic research, allowing the drug discovery capabilities of GSK to be applied to academic research at an early stage. Thirdly, we have identified small molecules capable of up-regulating expression of the human filaggrin gene, as a therapeutic strategy for eczema.  About 10% of the population are heterozygous carriers of a filaggrin loss-of-function mutation and therefore would benefit from increased filaggrin protein expression from the remaining normal copy of the gene.  This work, initially funded by MRC, is at the stage of medicinal chemistry and validation in animal models. 

References:

• Lane EB and McLean WHI (2008).  Broken bricks and cracked mortar – epidermal diseases resulting from genetic abnormalities.  Drug Discov Today: Disease Mechanisms, 5: 393-401 .
• Zhao Y et al., (2011) Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol. 131: 1045-1052 (PubMed ID: 21390048)