The acute respiratory distress syndrome (ARDS) represents a significant health hazard that is associated with high morbidity and mortality rates. Unfortunately, little progress has been made in advancing the treatment of ARDS. Phase I STTR funding supported the successful determination of a feasible formulation of tissue plasminogen activator (tPA) for pulmonary delivery. The successful outcome of phase I established the rationale for studies in animals to determine the safety of lung delivered; this is the primary objective of our phase II application. Thus, this application represents the advancement of work for pharmacological innovation in the treatment of ARDS and extends phase I studies to in vivo animal models to test the hypothesis that pulmonary delivery of tPA will be safe and well tolerated. To this end, the specific aims of this proposal are to: 1) Formulate pulmonary tPA for lung delivery. Mouse and human tPA will be formulated for pre-clinical toxicology and pharmacokinetic (PK)/pharmacodynamic (PD) studies; 2) Assess the tolerability of the pulmonary formulated tPA by assessing both acute (dose escalating) and chronic (repeated dose) toxicity as determined by utilization of a mouse model which will be subjected to pulmonary instillation and intravenous (IV) administration of tPA formulated for lung delivery. These experiments are designed to measure indicators of toxicity such as pulmonary injury, disruption in coagulation homeostasis and hemorrhage; and 3) Determine the PK and PD disposition of pulmonary delivered tPA.
This aim will be accomplished by measuring lung and systemic therapeutic protein concentrations following pulmonary and IV administration of the pulmonary formulation in a rat model. These experiments are designed to assess disruption in coagulation homeostasis (PD end point) in the context of systemic tPA concentrations that are achieved following high doses of tPA (toxicokinetics). The anticipated outcomes associated with the successful completion of the work proposed in this application are: 1) establishment of the safety profile of a pulmonary formulation; 2) the development of a risk probability model for the clinical situation; and 3) preparation of an IND application that is required for eligibility for an FDA Orphan Products Grant Application. The proposed Phase II project will complement and extend our Phase I work and will facilitate the development of a promising new, greatly needed therapeutic for the treatment of ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
Project #
2R42HL071439-02
Application #
6991733
Study Section
Special Emphasis Panel (ZRG1-RES-F (10))
Program Officer
Harabin, Andrea L
Project Start
2002-08-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$468,604
Indirect Cost
Name
Htd Biosystems, Inc.
Department
Type
DUNS #
039385799
City
Hercules
State
CA
Country
United States
Zip Code
94547
Lin, Swan; Racz, Jennifer; Tai, Melissa F et al. (2016) A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs. Pharm Res 33:72-82
Lackowski, Nicholas P; Pitzer, Josh E; Tobias, Meghan et al. (2010) Safety of prolonged, repeated administration of a pulmonary formulation of tissue plasminogen activator in mice. Pulm Pharmacol Ther 23:107-14
Serkova, Natalie J; Van Rheen, Zachary; Tobias, Meghan et al. (2008) Utility of magnetic resonance imaging and nuclear magnetic resonance-based metabolomics for quantification of inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 295:L152-61
MacLaren, Robert; Stringer, Kathleen A (2007) Emerging role of anticoagulants and fibrinolytics in the treatment of acute respiratory distress syndrome. Pharmacotherapy 27:860-73