Acute lung injury (ALI) or Acute Respiratory Acute Respiratory Distress Syndrome (ARDS) are characterized by an increased permeability of the alveolar-capillary barrier resulting in lung edema with protein-rich fluid, thus resulting in impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and bronchoalveolar space. The incidence of ALI/ARDS is high (200,000 per year in the US) and the overall mortality remains very high (up to 40%) Despite all innovations in intensive care medicine. There are currently no effective pharmacological interventions for this devastated disease. There is a clear unmet medical need that urgently call for a novel treatment targets and agents. ALI can be triggered by multiple direct or indirect environmental causes, such as pneumonia, drowning, sepsis, pancreatitis, trauma and reperfusion injury. Reperfusion injury, also known as primary graft dysfunction (PGD), is a severe form of ALI that is a major cause of early morbidity and mortality encountered after lung transplantation. PGD is diagnosed by pulmonary edema with diffused alveolar damage that manifests clinically as progressive hypoxemia with radiographic pulmonary infiltrates. there are no FDA approved drugs for PGD after lung transplantation to date. We have discovered the inhibition of Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) 2 and 3 reduces pulmonary edema and mortality in two mouse ALI models through a highly novel mechanism of action. Genetic loss of MAP3K3 in myeloid cells and MAP3K2 in hematopoietic cells (DKO) protects mice from pulmonary edema and death in ALI models. More importantly, we discovered that an FDA-approved oncology drug pazopanib potently inhibited MAP3K2/3 and could recapitulate the phenotypes of MAP3K2/3 deficiency both in vitro and in vivo, including those in the ALI models. Together with human relevant evidence, we believe that pazopanib can be repurposed for treatment of ALI/ARDS. In this SBIR Phase 1 project, we aimed to develop new formulation of pazopanib and provide proof of concept and dose dependence response in a mice ALI model. There are 3 main objectives for this SBIR Phase 1 project: (1) To identify a new IV formulation of pazopanib, which will be suitable for animal models and human clinical trials. (2) To demonstrate desire PK profile and (3) efficacy in the mouse ALI PD model in a dose dependent manner. The desirable outcome of this SBIR Phase 1 project will provide critical data to warrant a SBIR Phase 2 project, which will focus on Pre-IND enabling studies toward human clinical trials.
