atopic eczema, asthma and allergy Irwin McLean Centre for - PowerPoint PPT Presentation

Broken skin barrier is a key driver of atopic eczema, asthma and allergy Irwin McLean Centre for Dermatology & Genetic Medicine Division of Molecular Medicine University of Dundee Scotland

Skin – the largest organ

The epidermis – a super-tough, self-renewing tissue Stratum corneum Epidermis Dermis Keratinocytes

Skin barrier function Pathogens Allergens Irritants Stratum corneum Skin barrier H 2 O

The Filaggrin gene 38: 337-342, March 2006 From Ichthyosis Vulgaris… 38:441-446, April 2006 …to Atopic Eczema, Asthma etc 39:650-654, April 2007

Ichthyosis vulgaris • Most common monogenic skin disorder • Dry, scaly skin, worse in winter/dry climate • Hyperlinearity of palms/soles; keratosis pilaris • ~1% of the UK population have full form • >10% have a sub-clinical form • Evidence for defect involving filaggrin – Biochemistry – Genetic mapping • Large repetitive gene • Difficult to sequence • Many IV patients have eczema!

Atopic dermatitis • Atopic dermatitis (= “eczema”) • Affects >20% of children in developed nations • Incidence has increased in recent decades • Often accompanied by other allergic diseases (atopic disease, atopy) – Eczema – Food allergies (30%) – Asthma (50%) – Rhinitis (hay fever; 70%) • “Atopic march” • Healthcare burden US$ billlions

Filaggrin protein Profilaggrin 10-12 full filaggrin repeats N C 2x partial filaggrin repeats S100 domain B domain Unique C-terminus

Filaggrin - filament aggregating protein Epidermal filaggrin staining Keratin aggregation Processed Filaggrin (37 kDa) Proteolysis Profilaggrin (>400 kDa) Keratin filaments

“Natural moisturizing factor” Epidermal filaggrin staining Hygroscopic amino acids Further proteolysis Chemically modified filaggrin Peptidyl arginine deiminases Keratin aggregation

Filaggrin – a multi-functional skin barrier protein H 2 O RETENTION NMF pH UV PROTECTION ANTI-MICROBIAL Natural Moisturising Factor BARRIER FORMATION Filaggrin INERT Profilaggrin

FLG is a large, highly repetitive gene on 1q21.3 FLG gene 15 bp 153 bp 13 kb (or variant sizes of 14 kb or 15 kb) FLG Protein domains encoded 10-12 near-perfect 324 amino acid repeats 2 imperfect repeats

Irvine, McLean, Leung NEJM 2011 Aileen Sandilands, Frances Smith, Toshifumi Nomura, Huijia Chen

Irvine, McLean, Leung NEJM 2011 Alan Irvine, Irwin McLean, Donald Leung, NEJM (2011)

Filaggrin function and inherited deficiency “Normal” ~89% UK population 1x filaggrin mutation ~10% UK population ~8x risk eczema 2x filaggrin mutations ~1% UK population ~150x risk eczema

2x copies = 1.7x risk of AD 10 repeats 11 repeats 2x copies = 0.6x risk of AD 12 repeats

Filaggrin upregulation therapy

Most filaggrin-related eczema patients carry a single null mutation FLG FLG

Drug Discovery in Dundee Cutaneous Drug Discovery Portfolio: CDDP Paul Irwin Alan Mike Wyatt McLean Fairlamb Ferguson Target Discovery Drug Lead Validation Partnering selection Fully Potential Industrial Proof of Informatics Clinically Drug Target validated partners and concept and useable molecular PPP partners Genetic/chemi functional therapeutics data cal/animal genomics package model

Filaggrin expression in keratinocytes treated with chemical library Robyn Hickerson, Pam Robertson

Human filaggrin – luciferase transgenic mice Xenogen IVIS 200 live animal imaging Luciferase IMF footpad

Human filaggrin – luciferase transgenic mice Untreated Treated Vehicle only Vehicle plus Compound

Skin barrier function Pathogens Allergens Irritants Stratum corneum Skin barrier H 2 O

Impaired skin barrier function Pathogens Allergens Irritants Stratum corneum H 2 O Allergic immune response Eczema

Thanks

Alan Irvine MD

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