PURPOSE: To assess the efficacy of the novel clinical formulation of fenretinide (LAU-7b) for the treatment of allergic asthma. To study the association between LAU-7b treatment in allergic asthma and the modulation of very long chain ceramides (VLCC). METHODS: We used two allergens (OVA and HDM) to induce asthma in mouse models and we established a treatment protocol with LAU-7b. The severity of allergic asthma reaction was quantified by measuring the airway resistance, quantifying lung inflammatory cell infiltration (Haematoxylin and eosin stain) and mucus production (Periodic acid Schiff satin). IgE levels were measured by ELISA. Immunophenotyping of T cells was done using Fluorescence-activated cell sorting (FACS) analysis. The analysis of the specific species of lipids and markers of oxidation was performed using mass spectrometry. RESULTS: Our data demonstrate that 10 mg/kg of LAU-7b was able to protect OVA- and HDM-challenged mice against increase in airway hyperresponsiveness, influx of inflammatory cells into the airways, and mucus production without affecting IgE levels. Treatment with LAU-7b significantly increased percentage of regulatory T cells and CD4+ IL-10-producing T cells and significantly decreased percentage of CD4+ IL-4-producing T cells. Our data also demonstrate a strong association between the improvement in the lung physiology and histology parameters and the drug-induced normalization of the aberrant distribution of ceramides in allergic mice. CONCLUSION: 9 days of 10 mg/kg of LAU-7b daily treatment protects the mice against allergen-induced asthma and restores VLCC levels in the lungs and plasma.

Department of Human Genetics McGill University Montreal Quebec Canada Program in Infectious Diseases and Immunity in Global Health McGill University Health Center 1001 Decarie Boulevard Room EM3 3211 Montreal Quebec H4A 3J1 Canada

Department of Human Genetics McGill University Montreal Quebec Canada Program in Infectious Diseases and Immunity in Global Health McGill University Health Center 1001 Decarie Boulevard Room EM3 3211 Montreal Quebec H4A 3J1 Canada Department of Medicine Division of Experimental Medicine McGill University Montreal Quebec Canada

Department of Human Genetics McGill University Montreal Quebec Canada Program in Infectious Diseases and Immunity in Global Health McGill University Health Center 1001 Decarie Boulevard Room EM3 3211 Montreal Quebec H4A 3J1 Canada Division of Immunology Department of Pediatrics Boston Children's Hospital Harvard Medical School Boston MA USA

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Program in Infectious Diseases and Immunity in Global Health McGill University Health Center 1001 Decarie Boulevard Room EM3 3211 Montreal Quebec H4A 3J1 Canada Department of Medicine Division of Experimental Medicine McGill University Montreal Quebec Canada

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