Development of Apolipoprotein-based Therapeutics for Asthma

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Apolipoprotein E is a 34 kDa, 299 amino acid protein that folds into a helical horseshoe configuration which contains a distinct LDL receptor-binding domain, corresponding to amino acids 134 to 150 of the amino-terminus, as well as a major lipid-binding domain, corresponding to amino acids 244 to 272 of the carboxy-terminus. The amino-terminus of apolipoprotein E is comprised of a four amphipathic alpha-helices, with the LDL receptor-binding domain located in helix 4. Apolipoprotein E mimetic peptides, which correspond to the LDL receptor-binding domain, have been shown to bind LDL receptor family members and thereby suppress inflammation and neurotoxicity, as well as to mediate anti-viral effects. We have demonstrated that systemic administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130 149 of the full-length protein, can rescue the asthmatic phenotype of apoE knockout mice and attenuate the induction of house dust mite-induced asthma (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). Ongoing projects are further defining the role of apolipoprotein E and apolipoprotein A-I mimetic peptides as a potential new therapeutic approach for asthma. The pre-clinical data generated from this project demonstrating the efficacy of aerosolized delivery to the lung will be used to support future clinical trials of this approach in patients with severe asthma.