HLA Allele Specific Immune Modulation for Type 1 Diabetes

Project SummaryTypediabetesT Dresults from the immune mediated destruction of insulin producing beta cells within the pancreasT D is increasing in incidence and predictable with the measurement of T D associated autoantibodies from the peripheral bloodhoweverthere are no means to prevent the diseaseDespite the availability of exogenous insulinmany patients and families have difficulty attaining normal blood glucose control and thus remain at risk for devastating acutehypoglycemiaand long term complicationsAs suchit is estimated that T D accounts for $billion in healthcare costs each yearTo lessen the burden of disease and to better address the heterogeneity of the T Dmore specific and personalized therapies that treat the underlying autoimmunity of T D are needed for disease preventionTo address this gapImmunoMolecular TherapeuticsIMTwas founded to develop small molecule drugs such as the D enantiomer of methyldopaMDOPAas an oral immunotherapeutic approach for the preservation of residual beta cell function in T DHuman leukocyte antigenHLAgenes confer significant genetic risk for T D with recent studies implicating HLA DQrestricted T cells in disease pathogenesismaking it an important therapeutic targetDQis present inof all T D patients and those at riskPreviouslya novel pathway to control the underlying T cell mediated autoimmunity in T D was identifiedwhich involves blocking DQwith MethyldopaAldometLMDOPA is an FDA approved drug for both children and adults with a well established safety profile as it has been used clinically over the lastyears to treat hypertension and pregnancy induced hypertensionA recent Phase Ib dose escalation clinical trial in recently diagnosed T D patientsnwith the HLA DQgene indicated that L MDOPA was safetolerable and confirmed the mechanism of actioni einhibited DQpeptide presentation to T cells including primary insulin specific T cellsHoweverthere are limitations with L MDOPA in terms of dosing frequencytwice to three times dailyand side effectsThe D enantiomer of methyldopa overcomes these limitationsUnlike the L enantiomerthe D enantiomer is likely not metabolized thereby eliminating many side effects as well as the anti hypertensive actionand has more potency to block DQin rodent experimentsWhile there are published reports using D MDOPA in humans many decades agothose studies were not done to today s scientific standards and are inadequate to qualify D MDOPA for an INDTo advance D MDOPA to the stage of an IND and further delineate the drug target effectwe propose the following specific aimsTo evaluate the direct drug target effecton and off rate to HLA DQfor D MDOPA compared to L MDOPAandTo evaluate initial toxicologypharmacology and metabolic properties of D MDOPAThese studies along with other preclinical work will establish the pharmacologysafety and tolerability necessary for IMT to file an IND for D MDOPA and then initiate human Phasetrials of this personalized medicine approach to treating typediabetes Project Narrative Typediabetes is an autoimmune disease that results from the body s immune system destroying insulin producing cells in the pancreasis dramatically increasing in incidence and is now predictableDiabetes treatment requires lifelong insulin administrationand patients are at risk for developing complicationseye diseasekidney diseasenerve damageand heart diseaseand low blood sugarsUnfortunatelytypediabetes is not yet preventable or curableOur proposed research seeks to develop safe and specific oral drugs to treat the underlying immune destruction of insulin producing cells to ultimately prevent typediabetesTo accomplish this we are targeting a specific marker on immune cellstermed DQinvolved in diabetes developmentThe small molecule drug directly binds and interferes with the function of DQ