A Novel Myeloperoxidase Inhibitor for Treating Multiple Sclerosis

Abstract Multiple sclerosisMSis an inflammatory demyelinating disease of the central nervous systemCNSIt is the most common autoimmune disease affecting the CNSAlthough much attention has focused on the immunological mechanisms in MSnew evidence suggests that oxidative stress also induces MS neuropathologyMyeloperoxidaseMPOis a powerful peroxidative enzyme that has long been considered a therapeutic target in MSTo inhibit MPO toxic oxidant production we designed N acetyl lysyltyrosylcysteine amideKYCand showed that KYC effectively reduced neurological disease severity scores in EAE mice by sealing the blood brain barrier and reducing myeloid cell recruitmentJ NeurochemPMIDOur current research suggests KYC reduces MPO dependent activation of neutrophilsand possibly other myeloid cells whose function and phenotype are linked to MPOKYC does notkillMPO activity rather it depletes MPOof its high energy iron bound peroxyl radicals thereby reducing oxidative damage to the CNSWhen KYC is presentit efficientlyshuttlesMPO radicals into the glutathione pathwayessentially turning MPO into a quasi catalase that effectively reduces oxidative stress in MSIn our published murine studies KYC was administered via intraperitoneali pinjectionwhich is not an acceptable delivery route in humansAdditional studies are required to determine if KYC administration by subcutaneouss cor intranasali nare as effective as i psince both s cand i nare routes of therapeutic delivery routinely used in humans with MSAfter optimizing KYC routes of deliverywe will do head to head comparisons of KYC to dimethyl fumarateDMFAccordinglythe goal of our SBIR Phase I studies isKYC administration via s cor i nis equal or superior to DMF in ameliorating EAE disease severityAimwill define clinically relevant KYC dosing regimensAimwill compare KYC therapeutic dosing to DMF therapeutic dosing in established EAE modelsMilestonesAimKYCs cor i ndecreases EAE severity equal to or better than i pKYCAimKYC reduces EAE disease severity equal or superior to DMFIf 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\STTR funding that will be used for contracting GLP labs to perform the preclinical safetypharmacokineticpharmacodynamic and toxicology studies to generate the data that are required for filing an IND with the FDA Project Narrative The goal of this Phase I SBIR application is to determine the feasibility of using N acetyl lysysltyrosylcysteine amideKYCto reduce neurological pathology in multiple sclerosisMSMS is one of the most common neurological diseases in the United StatesDuring MSwhite blood cells move into the central nervous systemCNSbecome activated and release myeloperoxidasea potent oxidative enzyme that generates toxic oxidants that can damage brain and spinal cord cellsKYC s ability to inhibit myeloperoxidase reduces oxidative damage to the CNSreduces myeloid cell recruitment and allows the brain the time and opportunity to repair and regenerate