KYC Reduces Vasculopathy in Sickle Cell Disease

Project Abstract N Acetyl lysyltyrosylcysteine amideKYCis a novelbioengineered tripeptide inhibitor of myeloperoxidaseMPOtoxic oxidant productionDuringwe reported that KYC effectively inhibited MPO dependent oxidative damage to the vessel wall and improved vasodilatation in sickle cell diseaseSCDmicePMIDOur report was the first to demonstrate that MPO was a druggable therapeutic target for reducing vasculopathy in SCDThis is important because experts in the field think vasculopathy plays a causal role the mechanisms by which SCD increases life threatening occlusive events such as acute chest syndromeACSsilent cerebral infarctSCIand strokeClinical studies show that SCD induces vasculopathy and that vasculopathy increases in SCD with ageSuch clinical observations begin to explain why regular transfusion therapy is so effective at reducing the incidence of silent cerebral infarctSCIand stroke in children with SCD fromto andltbut not adultsWhile EndariL glutamineprotects RBC from oxidative damagereduces the incidence of acute chest syndromeACSin people with SCD by more thanfoldthe incidence of ACS in people with SCD is stillwell higher than that which can be achieved in SCD children with regular transfusion therapyandltWhat this means is additional mechanisms must be involved in how SCD increases life threatening events in adultsAs SCD increases vasculopathy and vasculopathy plays a causal role in the mechanisms by which SCD increases SCI and strokewe reasoned that KYCa proven inhibitor of MPO oxidant productionmay also be effective agent for reducing sickle RBC retention in lungs and cerebral events in adults with SCDAccordinglythe goal of this revised proposal is to determine KYC pharmacokineticsAimthe feasibility of using KYC to reduce sickle RBC retention in the lungsone of the first steps towards vasocongestionAimas well as cerebral events in the brains of SCD miceAimIf proof of concept is established in these SBIR Phase I studiesReNeuroGenLLC will design and develop a realistic and compelling Phase II planraise capital from angel investors and apply for Phase II SBIR funding that will be used for contracting GLP labs to perform the preclinical safetypharmacokineticpharmacodynamic and toxicology studies to generate data required for filing an IND with the FDA for using KYC to treat vasculopathy to reduce the risk of life threatening events in the lung and brains vasculopathy in people with SCD Project Narrative The goal of this Phase I SBIR application is to determine the feasibility of using N acetyl lysysltyrosylcysteine amideKYCto reduce vascular disease in sickle cell diseaseSickle cell disease has been shown to induce vascular disease by a variety of different mechanismsOur laboratory has shown that myeloperoxidase plays an important and causal role in how sickle cell disease induces vascular diseaseOur new drugKYC inhibits myeloperoxidase and reduces vascular disease induced by sickle cell disease which we think will also reduce retention of sickle red blood cells in lungs and reduce the number of small cerebral infarctions that occur in sickle cell disease