Targeting lipid rafts for treatment of asthma

PROJECT SUMMARY
Asthma, characterized by airways obstruction with symptoms of wheezing, shortness of breath, chest tightness
and consequently cough, remains a significant health problem. While advances in bronchodilator, corticosteroid
and Th2-targeting therapy allow for well-controlled asthma in a large population of patients, subjects with severe,
corticosteroid resistant asthma require frequent hospitalizations and emergency care for life-threatening
conditions. In these patients, strong neutrophilic, Th1 and Th17 inflammatory responses, often to bacterial or
fungal pathogens, result in exacerbation of disease and steroid resistance. Importantly, many cellular immune
and inflammatory responses are initiated by receptors localized to lipid rafts, membrane microdomains
characterized by increased content of cholesterol and sphingolipids. In this proposal, a collaboration initiated
between Raft Pharmaceuticals LLC and the University of California San Diego (UCSD) seeks to fully evaluate
RFT001, a biologic that selectively interferes with lipid rafts in activated cells. Preliminary studies indicate that
inhaled RFT001 reduces lung inflammation and the number of mucus-producting cells in mice challenged with
house dust mite (HDM) allergen, as well as acute lung injury by bacterial lipopolysaccharide. We propose that
administration of RFT001 can inhibit the pathogenesis of both corticosteroid sensitive Th2 dependent asthma
(effects on lipid rafts in mast cells, B cells regulating IgE, Th2 cells, and epithelial cells expressing eosinophil
chemoattractants), as well as inhibit corticosteroid resistant severe asthma in a mouse model (by effects on lipid
rafts in Th1, Th17, and epithelial cells expressing neutrophil chemoattractants). In both preclinical models, the
UCSD team will examine efficacy of RFT001 in reducing airway hyperresponsiveness and immune and
inflammatory responses in bronchoalveolar lavage and the lungs. Raft Pharmaceuticals will determine exposure
margins for the described efficacy studies and will examine whether RFT001 demonstrates a reasonable safety
margin in a repeat dose safety study. Collective data from this proposal will determine utility and feasibility of
RFT001 for development as an asthma therapeutic.PROJECT NARRATIVE
Asthma remains a significant health problem, particularly in patients with the severe, corticosteroid resistant form
of diseases. Raft Pharmaceuticals will test the efficacy, exposure and preliminary safety of RFT001 representing
a novel class of inhaled biologics targeting lung inflammation.