SBIR/STTR Award attributes
Abstract SignificanceInfantile Pompe DiseaseIPDis an autosomal recessive glycogen storage disorder caused by a deficiency of acid alpha glucosidaseGAAleading to accumulation of glycogen in lysosomesprimarily in skeletalcardiac and smooth musclesUntreated IPD infants die within the firstyears of lifeEnzyme replacement therapyERTwith recombinant human GAArhGAAimproves survival and quality of lifebut the development of sustained anti therapeutic antibodiesATApotentially reduces ERT efficacyAll IPD patients who have no GAA protein expressioncirculating cross reactive immunologic materialCRIMnegativeare predicted to mount high titer ATAand are treated with an intensive Immune Tolerance InductionITIregimenWhile some CRIM positive IPD patients become tolerized to ERT over timeover one third of CRIM positive patients still develop treatment limiting ATAThere is currently no effective method for determining which CRIM positive patients are at risk of developing treatment limiting ATAand would therefore benefit from treatment with an ITI regimenThis project will validate a recently developed algorithmGAA iTEMfor predicting the risk of ATA development for individual IPD patientsin a retrospective study of clinical data and in vitro studies of GAA T cell epitopesHypothesisCRIM positive IPD patients are tolerized to their own residual native GAAnGAAbut may develop ATA to ERT with rhGAAUsing well established computational tools to identify T cell epitopes in rhGAA which are predicted to stimulate CDT cellsand thus promote a T dependent B cell response to rhGAApatients may be classified as high or low risk for the development of ATAT cell epitopes that are cross conserved between nGAA and rhGAAand other endogenous epitopesare unlikely to induce a T cell responseGAA iTEM currently predicts ATA riskusing the patient s HLA type and nGAA sequenceWe propose to improve GAA iTEM using newly accessible clinical data and samplesIn Specific AimCRIMIPD patients followed at Duke with defined ATA responses will be evaluated using GAA iTEM to generate a patient specific GAA Individualized T cell Epitope MeasureGAA iTEMscoreClinical and genetic factors will be used to refine the predictive toolwhich will be made available through a prototype graphical user interface to Duke clinicianswho will assess patient specific risk and deposit clinical data for future calibration of the prediction algorithmIn Specific AimGAA CDT cell effector and regulatory epitopes identified in silico will be evaluated for HLA bindingcytokine stimulationand generation of TregsOverall ImpactGAA iTEM will provide researchers with an individualized assessment of a patient s risk for developing treatment limiting ATA based on their HLA haplotype and nGAA mutationsimproving decision making regarding ITI treatmentOnce validatedthe new GAA iTEM would be used to assess ATA risk in a prospective studyand to develop ATA risk assessment tools for related genetic disorders PROJECT NARRATIVE Infantile Pompe DiseaseIPDis a glycogen storage disorder caused by a deficiency of acid alphaglucosidaseGAAthatwithout treatmentleads to death by cardiorespiratory failure within the first two years of lifeThe only treatment currently available is enzyme replacement with recombinant GAAbut many patients develop anti therapeutic antibodiesATAthat render the therapy ineffectiveThis project proposes the development and validation of a diagnostic tool to identify patients who are at high risk of developing treatment limiting ATA using personalized genetic informationwith the goal of assisting clinicians to tailor the implementation of immune suppressive therapy with potential long term adverse effects to only those IPD patients at higher risk of developing ATA
