Phase I Amount
$1,109,134
Bronchopulmonary Dysplasia (BPD) is the most common chronic respiratory disease in infants and is a devastating condition that disrupts the developmental program of the lung secondary to preterm birth. BPD affects neonates exposed to mechanical ventilation and, to date, there are no specific drugs available to prevent or treat this life-threatening condition. The pathologic hallmarks of BPD are hyperoxia-induced pulmonary inflammation, increased cell death, dysregulated angiogenic factors culminating in impaired alveolarization, dysregulated vascularization of the lung and pulmonary hypertension. AyuVis Research, Inc, is developing a novel class of low molecular weight natural oligosaccharide-derived small molecules which activate macrophage to a non-inflammatory phenotype via TLR4 signalling. In both mouse and preterm lamb BPD models, the lead candidate AVR-48 binds to TLR4 resulting in selective activation of the target cell to block inflammatory mediators in lung and upregulation of endogenous vascularization pathways improving lung vascularization/alveolization leading to improved lung function. Additionaly, it enhances production of certain host anti-inflammatory molecule such as IL-10 and growth factor VEGF with vascularization effects remaining local to lungs. AVR-48 also prevents the development of BPD associated pulmonary hypertension. We have demonstrated all these above mentioned therapeutic effects in two BPD models: intraperitoneal injection of AVR-48 prevents hyperoxia- induced BPD in a neonatal mice pup model at 10mg/kg dose and intravenous injection in invasive mechanical ventilator induced BPD in pre-term lambs at 3.0 mg/kg dose. In order to advance the lead candidate AVR-48, AyuVis is proposing three complimentary aims: (1) Determine safety and long-term efficacy in the preterm lamb model by testing whether prophylactic treatment with AVR-48 improves the long-term respiratory, cardiac and neurodevelopmental outcomes measured after 2 months of life to mimic 1-2 years of infant life; (2) Demonstrate anti-inflammatory effect of AVR-48 in human cord blood after LPS and hyperoxia challenges by measuring cytotoxicity, inflammatory and anti-inflammatory mediators and macrophage phenotypes (M1, M2, M1/M2); and (3) Determine toxicokinetic parameters in juvenile rats following GLP protocol that will be used to model human equivalent dose in clinic. These studies are expected to provide mechanistic and confirmatory efficacy data which would enable AVR-48 to progress to GMP manufacturing and file an Investigational New Drug application with the FDA.
Public Health Relevance Statement: NARRATIVE Bronchopulmunary Dysplasia (BPD) is a disease of pre-term infants whose lungs are injured upon exposure to excess oxygen from ventilators, impairing effective gas exchange in the lungs. Ayuvis Research is developing a novel class of immunomodulating compounds derived from chitin that decrease inflammation and improve lung vascularization as well as decrease pulmonary hypertension. Our objective is to test the efficacy of our lead compound in pre-term lamb model mimicking the physiology of ventilated preterm human infants and to further validate its effect in a series of animal and in vitro tests. Results of this research will lead to much needed prophylactic treatment for BPD and treatment for other life-threatening lung conditions.
Project Terms: Adrenal Cortex Hormones; Corticoids; Corticosteroids; Adult; 21+ years old; Adult Human; adulthood; Affect; Angiogenic Factor; Angiogenesis Factor; Animals; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Bacteremia; bacteraemia; bacterial sepsis; Brain; Brain Nervous System; Encephalon; Bronchopulmonary Dysplasia; chronic lung disease in infants; chronic lung disease in neonatal infants; chronic lung disease in neonates; chronic lung disease in newborns; chronic lung disease in prematurity; infant chronic lung disease; neonatal chronic lung disease; newborn chronic lung disease; Calcium; Cell Death; necrocytosis; Cells; Cell Body; Chitin; Clinical Trials; comorbidity; co-morbid; co-morbidity; Complication; Cessation of life; Death; Diagnosis; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Gases; Gestational Age; Chronologic Fetal Maturity; Fetal Age; Goals; Gram-Negative Bacteria; Grant; Human; Modern Man; Pulmonary Hypertension; Immunity; In Vitro; Incidence; Infant; Premature Infant; infants born premature; infants born prematurely; premature baby; premature infant human; preterm baby; preterm infant; preterm infant human; Infection; Inflammation; Intraperitoneal Injections; IP injection; intravenous injection; Interleukin-1 beta; Beta Proprotein Interleukin 1; IL-1 beta; IL-1 ß; IL-1-b; IL-1ß; IL1-Beta; IL1-ß; IL1B Protein; IL1F2; IL1ß; Interleukin 1beta; Interleukin-1ß; Preinterleukin 1 Beta; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Lead; Pb element; heavy metal Pb; heavy metal lead; Lung; Lung Respiratory System; pulmonary; Lymphocyte; Lymphatic cell; Lymphocytic; lymph cell; macrophage; MÏ; Molecular Weight; monocyte; Blood monocyte; Marrow monocyte; Mus; Mice; Mice Mammals; Murine; Oligosaccharides; O element; O2 element; Oxygen; Phagocytosis; Phenotype; Physiology; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Play; Production; Proteins; Common Rat Strains; Rat; Rats Mammals; Rattus; Research; Rest; Risk; social role; Role; Safety; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Testing; Time; Transforming Growth Factor beta; Bone-Derived Transforming Growth Factor; Milk Growth Factor; Platelet Transforming Growth Factor; TGF B; TGF-beta; TGF-ß; TGFbeta; TGFß; Transforming Growth Factor-Beta Family Gene; Universities; Up-Regulation; Upregulation; Utah; Vascularization; Mechanical Ventilators; Pulmonary Ventilators; Work; cytokine; Measures; Interleukin-10; CSIF; CSIF-10; Cytokine Synthesis Inhibitory Factor; IL-10; IL10; IL10A; Interleukin 10 Precursor; Gram-Negative Bacterial Infections; Outcome Measure; Ventilator; Premature Birth; Prematurely delivering; Preterm Birth; premature childbirth; premature delivery; preterm delivery; Umbilical Cord Blood; Cord Blood; fetal cord blood; Reactive Oxygen Species; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Investigational New Drug Application; Secondary to; Immunologist; improved; Prophylactic treatment; Prophylaxis; Mechanical ventilation; mechanical respiratory assist; mechanically ventilated; Clinical; Series; Adolescent; Adolescent Youth; juvenile; juvenile human; peripheral blood; Blood Serum; Serum; pediatric; Childhood; lung function; pulmonary function; Recovery; Orphan; hyperoxygenation; Hyperoxia; inflammatory mediator; Inflammation Mediators; NT mimic 1; mimic 1; neurotensin mimic 1; Lung damage; pulmonary damage; pulmonary injury; pulmonary tissue damage; pulmonary tissue injury; lung injury; Toxicokinetics; NOAEL; No-Observed-Adverse-Effect Level; Immunological response; host response; immune system response; immunoresponse; Immune response; Genetic Predisposition; Genetic Susceptibility; Inherited Predisposition; Inherited Susceptibility; genetic etiology; genetic mechanism of disease; genetic vulnerability; genetically predisposed; Genetic Predisposition to Disease; Exposure to; Inflammatory; dyscrasia; Dysplasia; Life; programs; Scientist; Clinic; Protocol; Protocols documentation; prophylactic; Techniques; respiratory; meetings; Lytotoxicity; cytotoxicity; experience; genotoxicity; early childhood; unborn; prenatal; novel; Agreement; Prevention; Reporting; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; TNF gene; Modeling; response; drug development; Cardiac Toxicity; Cardiotoxic; Cardiotoxicity; vasculogenesis; lung failure; pulmonary failure; Respiratory Failure; Molecular Interaction; Binding; VEGF; VEGFs; Vascular Endothelial Growth Factors; preventing; prevent; small molecule; Homolog of Drosophila TOLL; TLR4; Toll Homologue; toll-like receptor 4; TLR4 gene; Alveolar; Dose; Bolus; Bolus Infusion; Data; Antiinflammatory Effect; anti-inflammatory effect; Pathologic; Cardiac; Therapeutic Effect; Development; developmental; Pathway interactions; pathway; neonate; novel strategies; new approaches; novel approaches; novel strategy; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; Neonatal; Prevention approach; Approaches to prevention; surfactant; Impairment; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; mouse model; murine model; pup; in vitro testing; efficacy testing; Regimen; tissue repair; endothelial dysfunction; Pulmonary Inflammation; Lung Inflammation; Pneumonitis; preterm newborn; premature neonates; premature newborn; preterm neonate; Growth Factor; Growth Agents; Growth Substances; Proteins Growth Factors; antenatal; antepartum; Injections; lead candidate; human model; model of human; ventilation; lamb model; neonatal mice; chronic respiratory disease; chronic airway disease; Respiratory Disease; Respiratory System Disease; Respiratory System Disorder; antagonist
