Maternal Interventions to Reduce Asthma: Targeting Novel Endotypes in Early Life

Asthma is a common childhood disorder with a heterogeneous presentation, representing multiple disease endotypes with distinct underlying mechanisms. Understanding these mechanisms in early life can enable personalised asthma prevention, addressing a significant unmet medical need, but no asthma/wheeze endotypes have been identified in young children that can be targeted. My preliminary findings from untargeted plasma metabolomics profiling in the COPSAC2010 and VDAART birth cohorts showed that maternal oxylipins, particularly undetectable 12-HETE, are associated with a distinct asthma endotype. Further, preliminary data showed a primary preventive effect of n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation in pregnancy only among mothers with detectable 12-HETE levels, highlighting a potential for personalised prevention. The MIRA project aims to uncover the mechanisms behind this novel oxylipin-associated childhood asthma endotype and develop tailored prevention strategies. This involves measuring targeted oxylipin profiles and investigating the determinants of maternal oxylipins during pregnancy and their impacts on infant alveolar macrophages (AMs), airway microbiome, longitudinal metabolome and proteome, and asthma outcomes in COPSAC2010 and VDAART. The project will also explore personalised strategies involving prenatal n-3 LCPUFA exposure. Mechanistic studies using wild-type and ALOX15-/- transgenic mice will evaluate the effects and uncover the mechanism. A key innovation of this project is the development of dry blood spot (DBS) screening tool for pregnant women, enabling early risk stratification and personalised intervention. The project will engage in patenting, technology transfer, intellectual property protection, and prototype validation with industry partners, paving the way for integrating the screening tool into prenatal care to prevent childhood asthma before birth.