Treatment of Allergic Asthma with Fenretinide Formulation (LAU-7b) Downregulates ORMDL Sphingolipid Biosynthesis Regulator 3 () Expression and Normalizes Ceramide Imbalance.

Zona pellucida binding protein 2 () and ORMDL sphingolipid biosynthesis regulator 3 (), mapped downstream of , were identified as two genes associated with airway hyper-responsiveness (AHR). gene product has been shown to regulate the biosynthesis of ceramides. Allergic asthma was shown to be associated with an imbalance between very-long-chain ceramides (VLCCs) and long-chain ceramides (LCCs). We hypothesized that Fenretinide can prevent the allergic asthma-induced augmentation of gene expression, normalize aberrant levels of VLCCs and LCCs, and treat allergic asthma symptoms. We induced allergic asthma by house dust mite (HDM) in A/J WT mice and KO mice expressing lower levels of mRNA than WT. We investigated the effect of a novel formulation of Fenretinide, LAU-7b, on the AHR, inflammatory cell infiltration, mucus production, IgE levels, and ceramide levels. Although lower expression, which was observed in KO mice, was associated with lower AHR, allergic KO mice were not protected from inflammatory cell infiltration, mucus accumulation, or aberrant levels of VLCCs and LCCs induced by HDM. LAU-7b treatment protects both the KO and WT mice. The treatment significantly lowers the gene expression of , normalizes the VLCCs and LCCs, and corrects all the other phenotypes associated with allergic asthma after HDM challenge, except the elevated levels of IgE. LAU-7b treatment prevents the augmentation of expression and ceramide imbalance induced by HDM challenge and protects both WT and KO mice against allergic asthma symptoms. SIGNIFICANCE STATEMENT: Compared with A/J WT mice, KO mice with gene deletion have lower AHR and lower levels of expression. The novel oral clinical formulation of Fenretinide (LAU-7b) effectively lowers the AHR and protects against inflammatory cell infiltration and mucus accumulation induced by house dust mite in both KO and WT A/J mice. LAU-7b prevents overexpression in WT allergic mice and corrects the aberrant levels of very-long-chain and long-chain ceramides in both WT and KO allergic mice.