Methods to Decrease Susceptibility to Asthmatic Bronchoconstriction

Abstract

Asthma, a common chronic disease of the airways that affects airflow, is a complex genetic disorder. Non-allergic childhood asthma in humans has been often associated with polymorphisms in the ORMDL3 gene. ORMDL3 encodes one of the Orm transmembrane proteins that inhibit serine palmitoyl-CoA transferase (SPT), the enzyme catalyzing the rate-limiting step in the de novo synthesis of sphingolipids (SL). This suggests that Orm proteins negatively regulate the synthesis of sphingolipids (SL), but does not link this to asthmatic symptoms.

The inventors used two mouse models (pharmacologic inhibition and genetic deficiency) to show that reduced SPT activity induces an asthma-like phenotype in vivo. Agents that increase SPT activity and thus enhance de novo SL synthesis have the potential to normalize the airway hypersensitivity. One such example is inhibitors of the cystic fibrosis transmembrane conductance regulator protein (CFTR). Indeed, treatment with the CFTR inhibitor GlyH101 reduces airway reactivity in SPT-deficient mice as measured by bronchial reactivity in response to methacholine.

Benefit

The invention can lead to improved, personalized therapies for asthmatic conditions

Potential Application

Treatment of asthma with CFTR inhibitors

Treatment of asthma with agents that increase SL synthesis

Genetic profiling of the ORMDL3 gene to predict patients' responsiveness to bronchodilation therapies.