Simvastatin nanomedicine in ARDS and sepsis

Period of Performance: 08/01/2016 - 07/31/2017


Phase 1 STTR

Recipient Firm

Eunoia BIO Tech, LLC
Principal Investigator


Title: Simvastatin nanomedicine in ARDS and sepsisThe host response to severe infection, termed sepsis, affects more than 1 million Americans/yr, generatingannual direct costs exceeding $20 billion. Novel therapies are sorely needed to target maladaptive features ofthe host response that complement antimicrobial drugs and advances in supportive care. Microcirculatoryhyperpermeability 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 pathwayas a critical regulator of vascular barrier function. Sepsis markedly attenuates signaling by the receptor Tie2as 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 inhibitors?statins?as potent suppressors of Angpt-2. Simvastatin prevented leakage and death in experimental sepsis, but onlywhen Angpt-2 was present. We have elucidated an intracellular mechanism of action connecting HMG-CoAinhibition in the endothelium to the suppression of ANGPT2 gene transcription.Given orally to treat hypercholesterolemia, statins undergo extensive first-pass hepatic metabolism, resulting inpoor bioavailability. Higher statin doses can harm liver, muscles, and kidneys, limiting their utility as clinicalAngpt-2 suppressors. Utilizing Eunoia?s proprietary platform of self-assembling peptides (ESAP), we havedeveloped 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 issafe and there is no obvious toxicity yet observed with ESAPs. We hypothesize that nanoSimva will achievea superior efficacy/toxicity profile compared to unencapuslated compound. Successful completion of thisSTTR project will position our team to continue pursuing a first-in-man study for this first-in-kind approach toameliorate a major public health burden in the ICU. The knowldege gained from the present studies will enableus to compete for phase II STTR/SBIR support needed prior to IND submission.