Allergic inflammatory asthma, especially severe asthma, remains a major public health concern. There is a need to search for new biomarker(s) that may lead to the development of novel target therapy. We have recently shown an unusual elevation of phosphorylated MARCKS (phospho-MARCKS) in various asthmatic airways, as compared to lung tissues/cells from non-asthmatic ones. This elevation is especially evidenced in airway epithelia and inflammatory cells in these asthmatic tissues. We and others have shown previously that unphosphorylated MARCKS is able to retain PI3K and PIP2 in membrane. Upon phosphorylation, phospho- MARCKS is detached from the membrane, together with the release of PIP2 and PI3K to produce the secondary messenger, PIP3 that activates AKT signaling pathways, essential for pathogenic asthma airways. Preliminary studies have shown that the major Th2 cytokine, IL-13 is a stimulator for the phosphorylation of both MARCKS and STAT6, and various phospho-STAT6 dependent gene expression, such as CLCA1, exotoxin, and TSLP, etc, in airway epithelia. Through gain- and loss-of-function experiments, we further demonstrated the upstream nature of IL-13-induced MARCKS phosphorylation event ahead of IL-13-induced STAT6 phosphorylation and downstream induced expression of various signature genes. An oligopeptide, MPS, was developed to mimic MARCKS phosphorylation site domain (PSD) sequence for the inhibition of MARCKS phosphorylation in vitro. In addition, we were able to suppress both ovalbumin- and Alternate- induced allergic asthma in mice in vivo. The suppression also occurred on the inhibition of the homing of antigen-presenting cells, such as dentritic cells in vivo, in addition to the suppression of airway hyperreactivity, inflammation, mucous cell metaplasia and airway remodeling. Based on these developments, we have generated further a novel peptide, MPS-6413D, with increase potency and stability in vivo for allergic animal treatment with no toxicity on control mice, or the cytotoxicity to normal primary human bronchial epithelial cells. Two aims are proposed in Phase I SBIR application. Aim 1 is to further extend the efficacy and the potency studies of the newly MPS-derived peptide, MPS-6413D, on the suppression of house dust mite chronically exposed allergic asthma in mice. Aim 2 is to carry out a similar pharmacological study on the efficacy and potency of MPS-6413D peptide on the suppression of guinea pig inflammatory asthma animal model. Completion 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 animals. Success 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.
Public Health Relevance Statement: PROJECT NARRATIVE Allergic airway disease, including asthma, is still difficult to treat. Initial studies have found unusual elevation of MARCKS phosphorylation in most asthmatic tissues and targeted suppression on this phosphorylation step by MPS-6413D peptide can suppress asthma in rodents. The study will demonstrate the therapeutic potential of MPS-6413D peptide on allergic animal models more relevant to human.
Project Terms: Acute; Adrenal Cortex Hormones; Agonist; Air Pollutants; airway epithelium; airway hyperresponsiveness; airway remodeling; AKT Signaling Pathway; Alanine; Allergens; Allergic; allergic airway disease; Alternaria; Amino Acids; Animal Model; Animals; Antigen-Presenting Cells; Asthma; asthmatic; asthmatic airway; asthmatic patient; base; Binding; Biological Markers; Bronchoscopy; Candidate Disease Gene; Cavia; Cell membrane; Cells; Chronic; Clinical assessments; clinical development; Clinical Treatment; commercialization; Consent; cytokine; cytotoxicity; Data Set; Dendritic Cells; Development; drug development; Drug Kinetics; Environment; Enzyme-Linked Immunosorbent Assay; Eotaxin; Epithelial Cells; Event; evidence base; Exhibits; Exotoxins; experience; experimental study; Extrinsic asthma; Fibrosis; Future; Gene Expression; genetic signature; Goals; Goblet Cells; Half-Life; Histologic; Homing; Human; Hydrophobicity; In Vitro; in vivo; Inflammation; Inflammatory; Inhalation; Injury; innovation; Interleukin-13; Lead; Legal patent; loss of function; lymph nodes; MARCKS gene; MARCKS-related peptide; Membrane; Metaplasia; microbial; Modeling; Modification; Mucins; Mucous body substance; Mus; N-terminal; Nature; new therapeutic target; next generation; novel; off-patent; Oligopeptides; Organism; Ovalbumin; Particulate; Pathogenicity; Peptides; Pharmacologic Substance; Pharmacology Study; Phase; Phosphatidylinositol 4,5-Diphosphate; Phosphorylation; Phosphorylation Site; Process; Public Health; Publications; Pyroglyphidae; Reaction; Reporting; Research; response; Rodent; Signal Transduction; Small Business Innovation Research Grant; Smoke; Specimen; STAT6 gene; Structure of parenchyma of lung; success; Symptoms; targeted biomarker; Therapeutic; therapeutic evaluation; therapy development; Tissues; Toxic effect; Toxicology; treatment strategy; TSLP gene
