Targeting lipid rafts for treatment of asthma

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PROJECT SUMMARY Patients with severe asthma who display persistent bronchoconstriction and/or reduced lung function despite available bronchodilator, corticosteroid and Th2-targeting therapy develop significant morbidity, which severely impacts their quality of life owing to persistent symptoms, as well as frequent and life-threatening exacerbations. Aspects of severe asthma currently not managed by available therapies may display a strong inflammatory component driven by the innate and adaptive immune systems, particularly following viral exacerbations. Development of new therapeutic strategies targeting a wide range of inflammatory mechanisms, not only Th2 and Th1/Th17 responses, is needed to control severe asthma. Raft Pharmaceuticals proposes a new target for treatment of severe asthma – overabundant and clustered, pathological lipid rafts in bronchial epithelial and immune cells in asthmatics. Cholesterol-rich lipid rafts provide ordered plasma membrane domains, where receptors, ion channels and adaptor molecules can associate to form functional complexes. Large lipid rafts are required as the landing pad for microbes on host cells and for initiation of many inflammatory processes in bronchial epithelial and immune cells. We discovered apoA-I binding protein (AIBP) as a molecule that selectively targets the cholesterol depletion machinery to pathologic lipid rafts in inflammatory cells, without affecting homeostatic cellular function. The latter explains an exceptional safety profile of AIBP in mice and rats. In the Phase I of this grant, using mouse models of asthma, we demonstrated that administration of a biologic derived from the AIBP protein, was effective in an acute HDM model of asthma in mice, reducing airway hyperresponsiveness, airway eosinophilia, and expression of Th2 cytokines and epithelial alarmins. In a model of severe asthma, AIBP significantly reduced pulmonary neutrophilia. For Phase II proposal, a team of experts in biologic drug development and in preclinical assessment and clinical trials of therapeutic agents in asthma has been assembled to further the characterization of an improved AIBP sequence, RFT1124, as a development candidate for severe asthma. Specifically, we plan to manufacture and release RFT1124 drug product for efficacy and toxicology studies using cGMP-compatible processes and analytical assays. The efficacy of RFT1124 as an add-on therapy to standard-of-care inhaled corticosteroids and long-acting beta-agonists (ICS+LABA) will be tested in mouse models of asthma exacerbated by rhinovirus (RV) infection. In addition, we will use precision cut lung slices from asthmatics and non-asthmatics postmortem lung tissue to test the efficacy of add-on RFT1124 in ICS+LABA treatment in RV infected human airways. RNAseq studies will establish whether RFT1124 inhibits corticosteroid insensitive anti-inflammatory pathways and/or enhances corticosteroid sensitive pathways in RV infected human bronchial epithelial cells. Further, a non-GLP safety assessment of intranasal delivery of RFT1124 will be conducted to establish an estimate of safety margin and target organs. These results will be used to prepare for and conduct pre-IND (Type B) meeting with the FDA.