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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
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
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
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
Human filaggrin–luciferase transgenic mice
Xenogen IVIS 200 live animal imaging Luciferase IMF footpad
Impaired skin barrier function
Stratum corneum
H2O
Pathogens
Allergens
Irritants
Allergic immune
response
Eczema