Redefining the asthma treatment paradigm using a locally administered dual PI3Kgd inhibitor

Introduction Severe asthma can be dominated by either Th2/eosinophilic or Th17/neutrophilic pathology yet the specific endotype of a patient may not be clear/stable. We hypothesized that a locally administered PI3kγδ dual isoform inhibitor could provide a more effective and safe treatment paradigm. Methods Nanomolar PI3K inhibitors with u003e100-fold selectivity for γ, δ or dual γδ isoforms were evaluated following nebulization in the rat OVA allergic model. The effects of these inhibitors on innate and adaptive immune responses were evaluated in human cells isolated from GINA3/4 asthma or healthy subjects. Results Therapeutic treatment (4, 20 u0026 100μg/kg) within the OVA allergic model showed substantial efficacy of the dual inhibitor on bronchoalveolar lavage (BAL) mediator release (IL-5 and IL-13) and eosinophil/neutrophil influx – reducing all parameters u003e80% in the absence of measurable systemic exposure. Target engagement in the lung was confirmed using the PI3K pathway marker pS6 in BAL CD4+ T cells. In both healthy and asthmatic subjects, activation, degranulation and chemotaxis of peripheral blood eosinophils or neutrophils was PI3Kγ dependent. However, primed neutrophil respiratory burst exclusively required PI3Kδ. The release of either IL-5, IL-13 or IL-17 from peripheral T cells was PI3Kδ-dependent. CD4+ T cell differentiation toward the Th2 or Th1 phenotype and migration of CD4+ T cells within a 3D collagen matrix, were modestly impaired by mono-selective compounds but effectively inhibited by dual inhibiton. Conclusions Our results provide evidence that an inhaled dual PI3Kγδ isoform inhibitor could be a novel, effective and safer therapy for a broad range of severe asthma patients.