Final Report Summary - MORIAE (HUMAN AND MOUSE MODELS OF RHINOVIRUS INDUCED ACUTE ASTHMA EXACERBATIONS)
Respiratory virus infections are the dominant cause of asthma attacks (exacerbations) in both children and adults. Human rhinoviruses (RV) are the cause in the majority of these exacerbations. Despite this awareness the mechanisms of RV induced asthma exacerbations are poorly understood. We have developed a human rhinovirus challenge model in healthy control subjects, and in people with mild and moderately severe asthma to identify novel mechanism of disease and to determine relationships of these with disease outcomes in vivo. We have been able to successfully refine the existing challenge model (high virus dose in steroid naïve mild asthmatic subjects) to develop a new low dose challenge model as the best model of naturally occurring infections. We have also successfully inoculated a series of patients with moderate asthma requiring daily inhaled corticosteroid therapy. No adverse events occurred and no withdrawals from the study on safety grounds were necessary. This is the first time patients with moderate asthma have been inoculated with a virus. The refinements to this model that we have been able to accomplish has the dual advantage of investigating mechanisms in the most natural model possible, as well as developing a better model for testing of novel therapeutic approaches in the future.
Current techniques for sampling secreted mediators in the lungs such as bronchoalveolar lavage have limited effectiveness. Many secreted mediators of interest are diluted to such an extent by this procedure that they are no longer measurable at all. We have successfully developed a technique that permits the sampling of the lower respiratory tract via a bronchoscope without first diluting the sample. This technique utilizes an absorptive pad fixed to the end of a probe and has the potential to greatly aid our understanding of the underlying mechanisms of this and other diseases. We have successfully measured over 30 different mediators of interest and have related levels to the differing clinical and virological outcomes that we have already identified. We have termed these novel techniques "nasosorption" and "bronchosorption" for sampling minimally diluted airway lining fluid to permit measurement of molecules previously undetectable. A Company entitled "Mucosal Diagnostics Limited" COMPANY NO 07986765, to commercialise these methodologies was registered in March 2012.
To date we have confirmed type I IFNs are essential in the host response to rhinovirus infection and these interferons are deficient in people with asthma. A proof of concept pivotal human intervention studies with inhaled type I IFN has been successfully completed and inhaled IFN-beta has been licenced to AstraZeneca for further clinical development. Our successful development of a new low dose challenge human model in both steroid treated moderate and steroid naïve mild subjects also provides a new and optimal model of naturally occurring exacerbations, in which proof of concept pivotal human intervention studies with other new drugs in development for asthma attacks can be carried out.
We have identified approaches to block activity of IL-17, IL-25 and IL-33 as a novel therapeutic approaches for treatment/prevention of asthma exacerbations. Approaches to block activity of IL-17, IL-25 and IL-33 are now in preclinical and clinical development as novel therapeutic approaches for treatment/prevention of asthma exacerbations.
We have also discovered that type III IFNs are essential in the host response to rhinovirus infection and these interferons are deficient in people with asthma. We are in the process of setting up a new company to develop inhaled IFN-lambda as another novel treatment approach for asthma exacerbations.
We have established a new Company called "Therapeutic Frontiers Ltd" - COMPANY NO 09029209, registration date May 2014. The aim of this Company is to commercialise exploitation of this new human model of disease for testing new pipeline drugs targeting asthma exacerbations: http://therapeuticfrontiers.com(se abrirá en una nueva ventana)
Current techniques for sampling secreted mediators in the lungs such as bronchoalveolar lavage have limited effectiveness. Many secreted mediators of interest are diluted to such an extent by this procedure that they are no longer measurable at all. We have successfully developed a technique that permits the sampling of the lower respiratory tract via a bronchoscope without first diluting the sample. This technique utilizes an absorptive pad fixed to the end of a probe and has the potential to greatly aid our understanding of the underlying mechanisms of this and other diseases. We have successfully measured over 30 different mediators of interest and have related levels to the differing clinical and virological outcomes that we have already identified. We have termed these novel techniques "nasosorption" and "bronchosorption" for sampling minimally diluted airway lining fluid to permit measurement of molecules previously undetectable. A Company entitled "Mucosal Diagnostics Limited" COMPANY NO 07986765, to commercialise these methodologies was registered in March 2012.
To date we have confirmed type I IFNs are essential in the host response to rhinovirus infection and these interferons are deficient in people with asthma. A proof of concept pivotal human intervention studies with inhaled type I IFN has been successfully completed and inhaled IFN-beta has been licenced to AstraZeneca for further clinical development. Our successful development of a new low dose challenge human model in both steroid treated moderate and steroid naïve mild subjects also provides a new and optimal model of naturally occurring exacerbations, in which proof of concept pivotal human intervention studies with other new drugs in development for asthma attacks can be carried out.
We have identified approaches to block activity of IL-17, IL-25 and IL-33 as a novel therapeutic approaches for treatment/prevention of asthma exacerbations. Approaches to block activity of IL-17, IL-25 and IL-33 are now in preclinical and clinical development as novel therapeutic approaches for treatment/prevention of asthma exacerbations.
We have also discovered that type III IFNs are essential in the host response to rhinovirus infection and these interferons are deficient in people with asthma. We are in the process of setting up a new company to develop inhaled IFN-lambda as another novel treatment approach for asthma exacerbations.
We have established a new Company called "Therapeutic Frontiers Ltd" - COMPANY NO 09029209, registration date May 2014. The aim of this Company is to commercialise exploitation of this new human model of disease for testing new pipeline drugs targeting asthma exacerbations: http://therapeuticfrontiers.com(se abrirá en una nueva ventana)