In Vitro Evaluation of a Novel Drug on Airway Epithelial Cells Obtained From Participants With Severe Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Asthma is a long term disease of the lungs. In asthma patients the sensitive airway tubes
      narrow in reaction to something that irritates the airways such as allergens or environmental
      pollutants. There is currently no cure for asthma and new medicines or combinations of
      medicines are needed that will be of benefit to patients particularly those with a more
      severe disease.

      Activation of certain signal molecules inside the lung cells may participate in the
      development of asthma and the response to allergens. Blocking these signal molecules
      specifically with medicines might therefore be beneficial in the treatment of asthma. In this
      study we want to test a new medicine that specifically targets a subset of signal molecules
      that are associated with the allergen response in the lung. In particular, we want to test
      this medicine on cells obtained from the lungs of asthma patients. Understanding the effects
      of this new medicine on these asthmatic lung cells will give vital information on how this
      new medicine works before we can test it in asthma patients.
    

Detailed description: 
      Asthma and COPD are chronic inflammatory diseases of the airway although the precise cells
      and mediators involved are distinct. Both diseases are characterised by airway
      hyperresponsiveness (AHR) in response to exogenous stimuli such as allergens in asthma or
      environmental pollutants. There is currently no cure for asthma and new drugs or combinations
      of drugs are needed that will be of benefit to patients particularly those with more severe
      disease.

      Activation of JAK/STAT pathways may participate in the pathogenesis of asthma. STAT1 and
      STAT6 expression is elevated in animal models of asthma and in the lower airways of some but
      not all patients. STAT6 is activated by key cytokines involved in asthma such as IL-13 in
      primary human bronchial epithelial cells. In addition, baseline phospho-STAT1 and
      phospho-STAT6 levels are increased in systemic T cells from steroid naïve asthmatics and the
      Th2 cytokines IL-4, IL-13 and TSLP activate STAT1 and STAT6 in a number of airway cells. In
      animal models of allergen-induced AHR, airway inflammation including CXCL9 and CXCL10
      involves STAT1. In addition, STAT6 knockout mice have no response to IL-4, do not develop Th2
      cells in response to IL-4, and fail to produce IgE, bronchial hyperresponsiveness or BAL
      eosinophilia after allergen sensitization. The expression of CCL11, CCL17 and CCL22 also
      involves STAT6 in these models.

      Importantly, STAT1 is a critical signalling molecule involved in the production of type I
      IFNs (α/β), IFN-γ and for resistance to viral respiratory infections. JAK/STATs inhibitors
      have proved effective in clinical trials for rheumatoid arthritis and inflammatory bowel
      disease.

      Therefore, we propose to use the primary airway epithelial cell culture model grown at
      air:liquid interface (ALI culture) to evaluate the efficacy of a novel JAK/STAT inhibitor,
      VR588, against CP-690550 and fluticasone proprionate (FP) in suppressing inflammatory
      readouts induced by IL-13 and by TNF/IFN.
    

Intervention name(s): VR588
Intervention type(s): Drug
Intervention description(s): Evaluation of the efficacy of a novel JAK/STAT inhibitor, VR588, in isolated epithelial cells from asthma patients
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Epithelial Cells