The objective of the proposed project is to advance the development of novel peptides targeting MARCKS (Myristoylated Alanine-Rich C Kinase Substrate) protein as platform drug molecules for the treatment of Acute Lung Injury (ALI) and its more severe form, Acute Respiratory Distress Syndrome (ARDS), thereby providing the first pharmacologic therapeutic for this condition. ALI/ARDS is a major cause of respiratory failure; worldwide, over 1 million cases occur annually, with ~ 200,000 adult and 15,000 pediatric cases per year in the U.S. This disorder is characterized by a large influx of neutrophils to the lung as part of an acute inflammatory response, injury to epithelial and endothelial cell barriers, and pulmonary edema, all of which lead to respiratory failure. Treatment options are presently limited to mechanical ventilation, a supportive therapy which still results in an in-hospital mortality rate of ~40% in the U.S., with few survivors discharged to home due to residual pulmonary and brain damage incurred during the acute illness. There currently are no drugs approved for treatment of patients with ALI/ARDS. The annual cost to the U.S. healthcare system due to prolonged hospitalization and intensive medical intervention is over $5 billion dollars. Thus, the potential impact of developing a new drug that could reverse ALI/ARDS would be immense. BioMarck Inc has generated preliminary data in mice with ALI induced by IT instillation of LPS showing that inhalation of aerosolized N-terminal peptide inhibitors of MARCKS not only completely prevents ALI/ARDS when administered prior to the insult, but also reverses the inflammation and injury up to 36 hrs AFTER LPS instillation. Additional preliminary data show that the inhaled peptide, specifically BIO-11006 (an investigational drug with an active IND under which the FDA allows clinical trials in COPD patients) is rapidly metabolized after inhalation to a shorter, longer-lived peptide metabolite. We have synthesized this metabolite and labeled it BIO-10901. In ALI/ARDS, where the lung is severely inflamed and injured, metabolism of BIO-11006 could be severely compromised; thus, we believe that direct inhalation of the metabolite, BIO- 10901, will provide better efficacy than BIO-11006. We propose here to determine if BIO-10901, shows more efficacy than the parent BIO-11006 in reversing the progression of ALI/ARDS in the mouse LPS model (Aim #1A) and in a more patho-physiologically-relevant model, bacterial pneumonia, which replicates the most common cause of ALI/ARDS in human patients (Aim #1B). We hypothesize that BIO-10901 will be clearly superior to BIO-11006 in these experiments, and will exhibit a consistent pattern of 20% or greater reduction in inflammatory measures and disease progression in comparison to the reductions provided by BIO-11006.
Public Health Relevance Statement: Public Health Relevance: Acute Respiratory Distress Syndrome (ALI/ARDS) are major causes of respiratory failure; worldwide, over 1 million cases occur annually, with approximately 200,000 adult and 15,000 pediatric cases per year in the U.S. Treatment options are presently limited to mechanical ventilation, a supportive therapy which still results in an in-hospital mortality rate of ~40% in this country, with few survivors discharged to home because of residual pulmonary and brain damage incurred during the acute illness. There currently are no drugs approved for treatment of patients with ALI/ARDS. The objective of the proposed project is to advance the development of novel peptides targeting MARCKS protein as platform drug molecules for the treatment of ALI/ARDS, thereby providing the first pharmacologic therapeutic for this condition.
Project Terms: Acute; Adult; Adult Respiratory Distress Syndrome; Advanced Development; aerosolized; Aerosols; Bacterial Pneumonia; Brain; Brain Injuries; Breathing; Childhood; Chronic; Chronic Obstructive Airway Disease; Clinical Trials; comparative efficacy; cost; Country; Data; Disease; Disease Progression; Endothelial Cells; Epithelial Cells; Event; Exhibits; Goals; Healthcare Systems; Home environment; Hospital Mortality; Hospitalization; Human; human disease; improved; Inflammation; Inflammatory; Inflammatory Response; inhibitor/antagonist; injured; Injury; Intervention; Investigational Drugs; Label; Lead; Life; Lung; Lung Inflammation; lung injury; Lung Injury, Acute; Measures; Mechanical ventilation; Medical; Metabolism; Modeling; Mortality Vital Statistics; mouse model; Mus; myristoylated alanine-rich C kinase substrate; N-terminal; neutrophil; novel; novel therapeutic intervention; Parents; Patients; Pattern; Peptides; Pharmaceutical Preparations; prevent; Proteins; public health relevance; Pulmonary Edema; research study; Residual state; Respiratory Failure; Stimulus; Supportive care; Survivors; Therapeutic; Time
