Evidence-Based Targeted Suppression on Inflammatory Asthma by a Novel Peptide

PROJECT SUMMARY Allergic inflammatory asthmaespecially severe asthmaremains a major public health concernThere is a need to search for new biomarker sthat may lead to the development of novel target therapyWe have recently shown an unusual elevation of phosphorylated MARCKSphospho MARCKSin various asthmatic airwaysas compared to lung tissues cells from non asthmatic onesThis elevation is especially evidenced in airway epithelia and inflammatory cells in these asthmatic tissuesWe and others have shown previously that unphosphorylated MARCKS is able to retain PI K and PIPin membraneUpon phosphorylationphosphoMARCKS is detached from the membranetogether with the release of PIPand PI K to produce the secondary messengerPIPthat activates AKT signaling pathwaysessential for pathogenic asthma airwaysPreliminary studies have shown that the major ThcytokineILis a stimulator for the phosphorylation of both MARCKS and STATand various phospho STATdependent gene expressionsuch as CLCAexotoxinand TSLPetcin airway epitheliaThrough gainand loss of function experimentswe further demonstrated the upstream nature of ILinduced MARCKS phosphorylation event ahead of ILinduced STATphosphorylation and downstream induced expression of various signature genesAn oligopeptideMPSwas developed to mimic MARCKS phosphorylation site domainPSDsequence for the inhibition of MARCKS phosphorylation in vitroIn additionwe were able to suppress both ovalbuminand Alternateinduced allergic asthma in mice in vivoThe suppression also occurred on the inhibition of the homing of antigen presenting cellssuch as dentritic cells in vivoin addition to the suppression of airway hyperreactivityinflammationmucous cell metaplasia and airway remodelingBased on these developmentswe have generated further a novel peptideMPSDwith increase potency and stability in vivo for allergic animal treatment with no toxicity on control miceor the cytotoxicity to normal primary human bronchial epithelial cellsTwo aims are proposed in Phase I SBIR applicationAimis to further extend the efficacy and the potency studies of the newly MPS derived peptideMPSDon the suppression of house dust mite chronically exposed allergic asthma in miceAimis to carry out a similar pharmacological study on the efficacy and potency of MPSD peptide on the suppression of guinea pig inflammatory asthma animal modelCompletion of these studies will allow us to move to a phase II SBIR study with the focus on the efficacy of the peptide on the treatment of clinical specimens obtained from severe asthma patients with consent through bronchoscopy thermoplasty and the pharmacokinetics and toxicology studies in large and small animalsSuccess of these studies will lead further to the plan for the submission of IND based study to FDA and the future clinical assessment on this novel peptide based treatment strategy PROJECT NARRATIVE Allergic airway diseaseincluding asthmais still difficult to treatInitial studies have found unusual elevation of MARCKS phosphorylation in most asthmatic tissues and targeted suppression on this phosphorylation step by MPSD peptide can suppress asthma in rodentsThe study will demonstrate the therapeutic potential of MPSD peptide on allergic animal models more relevant to human