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

Epidermis Dermis Stratum corneum Keratinocytes

Skin barrier function

Stratum corneum

H2O

Skin barrier Pathogens Allergens Irritants

38: 337-342, March 2006 38:441-446, April 2006 39:650-654, April 2007

From Ichthyosis Vulgaris… …to Atopic Eczema, Asthma etc

The Filaggrin gene

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 N C

S100 domain B domain 10-12 full filaggrin repeats 2x partial filaggrin repeats Unique C-terminus

Proteolysis

Profilaggrin (>400 kDa) Keratin filaments Processed Filaggrin (37 kDa) Keratin aggregation

Filaggrin - filament aggregating protein

Epidermal filaggrin staining

Peptidyl arginine deiminases

Chemically modified filaggrin Keratin aggregation

“Natural moisturizing factor”

Further proteolysis

Hygroscopic amino acids

Epidermal filaggrin staining

NMF Profilaggrin Filaggrin Natural Moisturising Factor

INERT BARRIER FORMATION H2O RETENTION pH UV PROTECTION ANTI-MICROBIAL

Filaggrin – a multi-functional skin barrier protein

FLG is a large, highly repetitive gene on 1q21.3

FLG gene Protein domains encoded

10-12 near-perfect 324 amino acid repeats 2 imperfect repeats

15 bp 153 bp 13 kb (or variant sizes of 14 kb or 15 kb)

FLG

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

10 repeats 11 repeats 12 repeats

2x copies = 1.7x risk of AD 2x copies = 0.6x risk of AD

Filaggrin upregulation therapy

Most filaggrin-related eczema patients carry a single null mutation

FLG FLG

Clinically useable therapeutics Discovery Target selection Potential Drug Target Validation Proof of concept Genetic/chemi cal/animal model Partnering Drug Lead Industrial partners and PPP partners Informatics and functional genomics Fully validated molecular data package

Mike Ferguson Alan Fairlamb Paul Wyatt

Drug Discovery in Dundee

Irwin McLean

Cutaneous Drug Discovery Portfolio: CDDP

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 Vehicle plus Compound Vehicle only Treated

Skin barrier function

Stratum corneum

H2O

Skin barrier Pathogens Allergens Irritants

Impaired skin barrier function

Stratum corneum

H2O

Pathogens Allergens Irritants Allergic immune response

Eczema

Thanks

Alan Irvine MD

Thanks