Dermal models

Preclinical CRO Services for

Inflammatory Diseases of the Skin

 

Dermatological diseases or symptoms, including but not restricted to skin inflammation , affect patients’ lives, not only from a medical, but also from a social point of view. Rodent models of skin inflammation are helpful to decipher the mechanisms of disease triggering or sustaining in patients.

Oncodesign Services offers access to several standard preclinical models addressing a variety of skin pathologies, and provides CRO support for de novo development of new skin inflammation models recently described in literature.

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Typical readouts for skin inflammation

In vivo readouts : 

  • Clinical scoring
  • Body weight
  • Real-time scratching (itch)

Ex vivo readouts : 

  • Fibrosis score
  • Histopathology
  • Biomarker/drug monitoring
  • Gene expression in skin, by qPCR/dPCR
  • Trans-epithelial water loss (TEWL)

Discover Oncodesign Services offers for skin inflammation diseases

  • Ex Vivo assays

    Primary human skin explants from healthy donors are used in a Franz cell device and treated either in the top chamber to simulate topical application or in the bottom chamber to simulate systemic exposure.

    Typically used to analyze:

    • Target engagement
    • Skin barrier functionality
    • Biomarker expression or inflammatory response, typically by PCR.

    Dermal-Ex Vivo Human Skin FranzCell photo

  • In vitro capabilities
    • Human primary keratinocytes
      • Assays: IL-8 secretion
    • Human reconstituted epidermidis (3D)
      • Assays: Stimulation of inflammatory pathways
      • Co-culture with bacterial supernatant │
      • Differentiation │ Proliferation │Triglyceride synthesis
    • Human sebocytes
      • Assays: Triglyceride synthesis
  • In Vivo models

    Oncodesign Services has developed several robust models of skin diseases available as CRO services to support your R&D programs.

    This is a non-exhaustive list, get in touch if you cannot find your desired model in the list.

    • Psoriasis model in mice, induced by Imiquimod
    • Skin scleroderma/fibrosis model in mice, induced by Bleomycin, Topoisomerase-I peptide-loaded dendritic cells, Topoisomerase-I and CFA
    • Atopic dermatitis model in mice, induced by Calcipotriol, DNFB or HDM
    • Pruritogen itch model in mice, induced by Chloroquine, Substance P or Imiquimod
    • Acnea model in rats and mice, induced by Sebaceous gland atrophy

Exemple : ex vivo human skin biopsy

Dermal-GeneExpression ex vivo Human Skin TNFaTreatment_EDE
  • Fresh human skin body
  • TNFα (10mg/mL) added to the Franz cell lower chamber
  • Induction of mild inflammatory gene response (Taqman qPCR) after 24h
Dermal-GeneExpression ex vivo Human Skin TNFa+ClobetasolTreatment
  • Topical Clobetasol (corticosteroid) treatment is able to downregulate TNFα -induced gene expression (gel>cream)

Case studies for skin inflammation

 

  • #1 : Acute Itch

    Real time scratching monitoring in mice

    The neuronal pathway leading to the generation of a scratching signal is different from the pain transmission pathway.

    CRO Services for acute itch models are based on intra-dermal inoculation of a pruritogen agent:

    • Chloroquine
    • Substance P
    • (alternatively, topical Imiquimod can generate itch)

    The response typically has a very fast onset & transient (<60min)

    Data acquisition platform used for recording os cratching events (numbers and duration)

         

     

    Evaluation of test compounds on itch relief :

    • Test compounds are applied topically 3 hours before itch induction.
    • The evaluation of NK-1 antagonist is in the substance P-introduced itch model

     

    • Dose-response valuation of two test compounds in the Chloroquine-induced itch model
  • #2 : House Dust Mite (HDM)-Atopic Dermatitis (AD) mouse model

    Topical application of HDM to BALB/c mice induces epidermis and dermis thickening & recruitment of inflammatory cells (eosinophils, mast cells and CD4+ cells).

    This model is useful for testing the efficacy of compounds targeting general skin inflammation.  HDM are applied directly on skin and the area is bandaged. The bandage is regularly replaced  over the course of several weeks.

     

  • #3:  Calcipotriol-induced atopic dermatitis in mice

    Topical application of Calcipotriol to BALB/c mice (BID from D0 to D9) induces changes in skin morphology and inflammation resembling immune perturbations observed in acute lesions of atopic dermatitis in patients.

    Topical drugs showed protective effects on skin clinical score by reducing epidermis and dermis hyperplasia.

    • Betamethasone (steroid anti-inflammatory drug)
    • Ruxolinitib (JAK1/JAK2 inhibitor)

     

  • #4 : TH17 cell-targeting drugs reduce psoriasis-related inflammation

    Psoriasis can result as dysregulation of the TH17 pathway:

    • TH1 to TH17 cell differentiation critically depends on the RORgt transcription factor
    • Phosphodiesterase-4 (PDE4) is critical for the release of IL-12, IL-23 and TNFa
    • Test compounds acting on RORgt (antagonist) and PDE4 (inhibitor) have demonstrated efficacy in psoriasis

     

    Psoriasis models consistently respond to oral and topical drugs showing clinical efficacy in psoriatic patients:

    • Oral drugs: Apremilast (PDE4 inhibitor), Monomethyl Fumarate (NFE2L2 inhibitor), Tofacitinib (JAK inhibitor)
    • Topical drugs: Clobetasol (corticosteroid), RORgt antagonist, AN2728 (PDE4 inhibitor)