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2004 PC Project Grant Award

W.H. Irwin McLean, Ph.D., D.Sc. and Frances Smith, Ph.D.

University of Dundee Scotland

Project Title:

Drug discovery for the treatment of Pachyonychia congenita

Biography

W.H. Irwin McLean received his Ph.D. and D.Sc. in Human Genetics from Queens University, Belfast. From 1992-1996 he completed Postdoctoral research with the CRC Cell Structure Research Group at the   University of Dundee, UK. From 1996-1998 he was Associate Professor of Dermatology & Cutaneous Biology at Jefferson Medical College, Philadelphia.

Since 1998 he has been the Wellcome Trust Senior Research Fellow & Professor of Human Genetics

He is one of the researchers who first identified the specific gene mutations relating to Pachyonychia congenita.

Frances Smith received her B.Sc. in biochemistry from the University of St. Andrews and her Ph.D. in Dermatology from the University of Edinburgh in the UK.   Her post-doctoral training continued in the CRC Cell Structure Research Group at the University of Dundee.   She also worked as a Research Assistant Professor in the Epithelial Genetics Group in the Department of Dermatology and Cutaneous Biology at Jefferson Medical College in Philadelphia.   She is currently working in the Epithelial Genetics Group, Human Genetics Unit at Ninewells Hospital and Medical School in Dundee, UK.

Her research interests are focused on the molecular genetics of epithelial fragility disorders and include the identification of new genes and associated disorders as well as the longer term aim of developing gene therapy strategies.

Abstract

The two major variants of pachyonychia congenita, PC1 and PC2, are caused by inherited defects in four keratin genes called K6a, K6b, K16 and K17.   PC1 is caused by mutations in the K6a or K16 gene; whereas PC2 is caused by defects in K6b or K17.   Three of the PC genes were first described by this research group.   There are more than 50 keratin genes in the human genome and to date, 19 have been linked to human disorders.   Of these keratin disease genes, the four that cause PC are unusual because they can be switched on and off in a number of natural situations.  

For example, they are switched on when the skin is wounded and switched off again when the wound is fully healed.   UV light and certain chemicals are also known to activate these genes and again, once these agents are removed, they are switched off again.   From studies in genetically modified mice, it is known that the K6a gene can be completely knocked out without causing any disease and it is thought that K6b and other keratins can compensate for its absence.   Thus, if a chemical could be found that inhibits the expression of K6a in a fairly specific manner, it could be developed as a drug to switch off the K6a gene in PC1 patients carrying a K6a mutation.  

In Dundee University, UK, a drug discovery facility has recently been set up, equipped with state-of-the-art robotics and large libraries of chemical compounds, to enable identification of new drugs.   Here, we will engineer human skin cells that will express a fluorescent signal under the control of the K6a gene.   We have one drug that we know can increase the activity of the K6a gene, which will allow us to demonstrate that our cells are capable of identifying drugs that act on this gene.   Using this cell line, we will screen an initial 5000 test drugs for those that can switch on or off the K6a gene.  

Drugs that can inhibit the activity of the K6a gene have the potential to treat PC1 and these will be chosen for further study.   The libraries are constructed in a way that allows rapid examination of an additional 500-1000 chemical variants of any chemicals showing the desired effect.   Compounds that increase K6a activity may be useful for treatment of other keratin disorders and these will be earmarked for study in other projects but will not be studied further here.   In the longer term, we aim to screen more than 32,000 test drugs as well as the available variants of the most promising ones.   The most efficacious and specific compounds we identify will be tested in a transgenic mouse model of PC1 being developed in parallel by Dr Dennis Roop in Houston.   Those which work well and are safe in the animal model will be developed for topical or systemic treatment of PC1 in humans.