Drugs ～Others～

Development of repair therapy for skin barrier function
by product lipids of novel lipase
Department of Bio-system Pharmacology, Graduate School of medicine,
Osaka University

Principal
Investigator

Associate Professor Ryuichi OHGAKI

Project Outline
Novel lipase-like protein SLIP, an essen
framidesIntercellular space of stratum corneum, which locates at theoutermost layer of the epidermis in skin, is ﬁlled with lamellar
structures of lipids mainly composed of ceramides. This
intercellular lipid lamellae is essen al for the “Skin barrier
fun on" to protect our body from physical damage, chemicaland biological irrita on, and dissipa on of water andelectrolytes.
Epidermis
Physicaldamage

Intercellular lipid lamellae
Chemical andbiologicalirritants

Composition:

Gross
Changes in the ceramide contents ω-hydroxylacylceramides especiallyappearance
important for skin barrier function
Wild type SLIP-KO
Excessiveloss of water
via skin bytranspiration.

Transmission electron microscopy

Granularcell layer

Water,
Electrolytes

Pricklecell layer

Gene knockout of SLIP (Skin-speciﬁc lipase-like protein), anovel lipase speciﬁcally expressed in epidermis, causesof the skin barrier
and death shortly a er
disrupbirth due to excessive water evapora on in mouse. In thestratum corneum of SLIP-KO mice, the lipid lamellar structure
becomes unclear, and the permeability of water andmacromolecules is enhanced. Ceramides in a wide range ofsubclasses are reduced considerably.
Disrupted skin barrier function in SLIP-KO mouse

Ceremide46%
Cholesterol
26%
Fatty acid13%
Cholesterol-sulfate 4%

Stratum
corneumfactorPostnatal day1

LethalElias J. Invest. Dermatol. 96 (1991)

Basal celllayerMolecular structure modelDowning J. Lipid. Res. 33 (1992)

Ceramides subclasses reducedin SLIP-KO neonates
Cha et al. Int J Mol Med. 38 (2016)

Current therapeu c approaches to pathologically
impaired skin barrier func on

Drug discovery for novel skin barrier repair therapy

In diseases such as atopic derma
and ichthyosis, the skinbarrier f
on is disrupted due to abnormas in thehomeostasis of ceramides in epidermis. Topical agents
containing humectants, emollients, and occlusives are widelyused to compensate for the impaired skin barrier func on.
However, these treatments do not restore the physiological

SLIP is a puta ve transmembrane protein presen
domain extracellularly in cell layers including stratumcorneum. We are aiming to iden fy product lipid molecules ofSLIP, which are expected to have a func on of arranging ormaintaining ceramides in the lamellar structure, and todevelop a novel repair therapy f.

Ichthyosis vulgaris

Atopic dermatitis

Skin barrier complements

Pharmacotherapy
・Anti-inflammatory
agents: corticosteroids,
calcineurin inhibitors

・Anti-histamines
・Immunosuppressant・Anti-microbials
・Targeted therapy:

SLIP

Arrangement/maintenanceInto lamellar structure

・ Humectants:
glycerol, urea, lactic acid・ Emollients:
glycol/glycerol stearate,soy-derived sterols

・ Occlusives:

IL-4/13 inhibitors,
JAK inhibitors

petrolatum, dimethicone,mineral oils

・Aeroallergens
・Food allergens
・Contact allergens

Avoidance of irritants

Stratum
corneum

Ceramides

・Humectants
・Emollients・Occlusives

・Vitamin D3
・Salicylic acid

Product lipids

Substrates

SLIP

Removal or
suppression ofhyperkeratosis

Intercellular lipidlamellae

Intact skinbarrier function
Granularcell layer

Product lipids of SLIP are expected to restore the pathologicallydisrupted skin barrier function in atopic dermatitis and ichthyosis byrecovery of the ceramide homeostasis in intercellular lipid lamellae.

Partial compensation of impaired
skin barrier function※ Physiological skin barrier function is not restored.

Target diseases: Impaired skin barrier func�on (Atopic derma��s, ichthyosis vulgaris, etc.)
Patent informa
Not applied
Technical features: Unique treatment that restores the physiologic
Marketability: Atopic derma
revalence rate is up to a few percent of the popula
worldwide
Ichthyosis vulgaris – prevalence rate is 1 pa nt in 250 to 300 person.
Challenges in development: Cost for iden car
cal POC in disease models
Joint research and development-lipidomics analysis, disease models
Proposal for collabora111