Simvastatin nanomedicine in ARDS and sepsis The host response to severe infection, termed sepsis, affects more than 1 million Americans/yr, generating annual direct costs exceeding $20 billion. Novel therapies are sorely needed to target maladaptive features of the host response that complement antimicrobial drugs and advances in supportive care. Microcirculatory hyperpermeability may be a major determinant of multi-organ dysfunction and death in sepsis. We have investigated control mechanisms in the septic vasculature to implicate the Angiopoietin-Tie2 pathway as a critical regulator of vascular barrier function. Sepsis markedly attenuates signaling by the receptor Tie2 as an endogenous antagonist ligand called Angipoietin-2 is induced in the vascular endothelium. Indeed, inhibition of Angpt-2 rescues vascular leakage, lung injury, and death in sepsis models. We performed an unbiased drug-repurposing screen that identified HMG-CoA reductase inhibitorsstatins as potent suppressors of Angpt-2. Simvastatin prevented leakage and death in experimental sepsis, but only when Angpt-2 was present. We have elucidated an intracellular mechanism of action connecting HMG-CoA inhibition in the endothelium to the suppression of ANGPT2 gene transcription. Given orally to treat hypercholesterolemia, statins undergo extensive first-pass hepatic metabolism, resulting in poor bioavailability. Higher statin doses can harm liver, muscles, and kidneys, limiting their utility as clinical Angpt-2 suppressors. Utilizing Eunoias proprietary platform of self-assembling peptides (ESAP), we have developed a monodisperse and highly stable nanoparticle-based delivery system for simvastatin (nanoSimva). The unique simplicity of forming nanoSimva compared to other technologies including liposomal formulations, which are extremely difficult, makes it possible to get into patients very quickly, especially since the drug is safe and there is no obvious toxicity yet observed with ESAPs. We hypothesize that nanoSimva will achieve a superior efficacy/toxicity profile compared to unencapuslated compound. Successful completion of this STTR project will position our team to continue pursuing a first-in-man study for this first-in-kind approach to ameliorate a major public health burden in the ICU. The knowldege gained from the present studies will enable us to compete for phase II STTR/SBIR support needed prior to IND submission.
Public Health Relevance Statement: Despite tremendous advances in the supportive care for critically ill patients, the health burden of sepsis and acute respiratory distress syndrome (ARDS) remains stubbornly high, with over 250,000 deaths per year in the U.S. Sepsis, which can arise in adults and children from any kind of infection, has no effective adjunctive therapies; excessive leakiness in small blood vessels appears to be an early and progressive hallmark of sepsis and ARDS. Successful execution of this project that targets the hallmark of sepsis and ARDS would position this work closer to a first-in-man testing of a first-of-its-kind therapeutic approach.
Project Terms: 3-hydroxy-3-methylglutaryl-coenzyme A; Address; Adult; Adult Respiratory Distress Syndrome; Affect; American; Angiopoietins; ANGPT1 gene; ANGPT2 gene; antimicrobial; antimicrobial drug; Area; Attenuated; attenuation; Bacteremia; base; Biocompatible; Biodistribution; Biological Availability; Biotechnology; Blood Vessels; CCL4 gene; Cellular Assay; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Clinic; Clinical; Collaborations; Complement; cost; Critical Illness; cytokine; Development; Direct Costs; Disease; Dose; Doxorubicin; drug mechanism; Encapsulated; Endothelial Cells; Endothelium; Evaluation; experience; Extravasation; Falciparum Malaria; Formulation; Functional disorder; Funding; Genetic; Genetic Transcription; Health; histological stains; Hour; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; hypercholesterolemia; Immune response; Immunology; In Vitro; in vivo; Infection; Inflammation; Inflammation Mediators; inhibitor/antagonist; Injection of therapeutic agent; Investigational Drugs; Investigational New Drug Application; Kidney; Kinetics; Laboratories; Lead; Libraries; Ligands; Ligation; Lipids; Liposomes; Liver; liver metabolism; Lung; lung injury; man; Medical; medical schools; Methods; microbial; Modeling; Molecular; mouse model; Muscle; nanocarrier; nanomedicine; nanomolar; nanoparticle; novel; novel therapeutics; Organ; Paclitaxel; particle; Pathway interactions; Patients; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Polymers; Positioning Attribute; pre-clinical; Preclinical Drug Evaluation; preclinical efficacy; prevent; Production; Public Health; Puncture procedure; Receptor Protein-Tyrosine Kinases; Receptor Signaling; response; scale up; Sepsis; septic; Signal Transduction; Simvastatin; Small Business Innovation Research Grant; Small Business Technology Transfer Research; small molecule; Solid; Solubility; Supportive care; System; Systemic infection; Technology; Testing; Therapeutic; TIE-2 Receptor; Tissues; Toxic effect; Toxicology; Vascular Endothelium; Vascular Permeabilities; Work
