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