Professor Irwin McLean FRS FRSE FMedSci
The central focus of the McLean Lab is the study of human inherited diseases that affect epithelial cells and epithelial tissues. The epidermis is the largest and most complex epithelial tissue and includes a number of appendages such as hair, nail, sweat glands and sebaceous glands, each of which is a miniature epithelial organ system. For this reason, most of the genetic diseases we work on are within the field of dermatology, although we also have an active interest in the anterior corneal epithelium, oral mucosa and other epithelial tissues.
Much of our research to date has involved identification of the causative genes for epithelial disorders. These studies used a combination of candidate gene analysis focusing on molecules of the keratin intermediate cytoskeleton and its attachment or modification proteins, as well as a positional cloning approach using genome-wide genetic linkage analysis and recently, next generation sequencing methodology in collaboration with the Genome Sequencing Unit within the Division of Molecular Medicine.
More recently, we have become heavily involved in complex trait genetics, where we have used a combination of candidate gene, genetic linkage and case-control analysis methods to identify the gene encoding filaggrin as the first definitive predisposing gene for atopic eczema, the most common skin disorder with a strong genetic component. Filaggrin mutations not only predispose individuals to atopic eczema but also to atopic asthma, hay fever and other allergies, including peanut allergy. This work showed for the first time that antigen/allergen/irritant exposure via a defective skin barrier is the key first step in triggering a whole range of allergic conditions.
Our research currently centres on development of new treatments for selected disorders where tractable therapeutic pathways have been identified. Specifically, we are developing RNA-interference therapy systems for the inherited skin blistering disorder epidermolysis bullosa simplex (EBS), the most common and one of the most debilitating inherited keratin disorders. In a parallel, we are developing RNAi therapy systems and carrying out small molecule drug discovery for pachyonychia congenita (PC), a rare keratin disorder where painful thickening and blistering of the soles of the feet is highly painful for those affected. In the eye, we are developing siRNA therapy for corneal dystrophy.
We are also have a number advanced small molecule drug discovery programmes, which we have developed in collaboration with the Drug Discovery Unit, College of Life Sciences. One of these is aimed at improving expression of the filaggrin gene in the very common skin conditions ichthyosis vulgaris and atopic eczema. Another small molecule programme is aimed at treating genetic diseases caused by nonsense mutations, such as the severe skin recessive skin blistering disorder dystrophic epidermolysis bullosa.
Smith FJD et al., Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature Genetics 38:337-342 (2006).
Palmer CNA et al., Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genetics 38:441-446 (2006).
Sandilands A et al., Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nature Genetics 39:650-654 (2007).
Fallon PG et al., A homozygous frameshift mutation in the murine filaggrin gene facilitates enhanced percutaneous allergen priming. Nature Genetics 41:602-608 (2009).
Leachman SA et al., First-in-human Mutation-targeted siRNA Phase Ib Trial of an Inherited Skin Disorder. Molecular Therapy 8:442-446 (2010).
Irvine AD, McLean WHI, Leung DY (2011) Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365: 1315-1327 (PubMed ID: 21991953)
Brown SJ et al., Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 127:661-667 (2011).
Zhao Y et al., Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol 131:1045-1052 (2011).
Pohler E et al., (2012) Haploinsufficiency for AAGAB causes clinically heterogeneous forms of punctate palmoplantar keratoderma. Nature Genetics 44: 1272-1276