Simvastatin nanomedicine in ARDS and sepsis

Title Simvastatin nanomedicine in ARDS and sepsis The host response to severe infection termed sepsis affects more than million Americans yr generating annual direct costs exceeding $ 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 Tie pathway as a critical regulator of vascular barrier function Sepsis markedly attenuates signaling by the receptor Tie as an endogenous antagonist ligand called Angipoietin is induced in the vascular endothelium Indeed inhibition of Angpt rescues vascular leakage lung injury and death in sepsis models We performed an unbiased drug repurposing screen that identified HMG CoA reductase inhibitors statins as potent suppressors of Angpt Simvastatin prevented leakage and death in experimental sepsis but only when Angpt was present We have elucidated an intracellular mechanism of action connecting HMG CoA inhibition in the endothelium to the suppression of ANGPT 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 suppressors Utilizing Eunoia s 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 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 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