SBIR-STTR Award

Significance: Infantile Pompe Disease (IPD) is an autosomal recessive glycogen storage disorder caused by a deficiency of acid alpha-glucosidase (GAA), leading to accumulation of glycogen in lysosomes, primarily in skeletal, cardiac and smooth muscles. Untreated IPD infants die within the first 2 years of life. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) improves survival and quality of life, but the development of sustained anti-therapeutic antibodies (ATA) potentially reduces ERT efficacy. All IPD patients who have no GAA protein expression (circulating cross-reactive immunologic material [CRIM]-negative) are predicted to mount high titer ATA, and are treated with an intensive Immune Tolerance Induction (ITI) regimen. While some CRIM-positive IPD patients become tolerized to ERT over time, over one-third of CRIM-positive patients still develop treatment-limiting ATA. There is currently no effective method for determining which CRIM-positive patients are at risk of developing treatment-limiting ATA, and would therefore benefit from treatment with an ITI regimen. This project will validate a recently developed algorithm, GAA-iTEM, for predicting the risk of ATA development for individual IPD patients, in a retrospective study of clinical data and in vitro studies of GAA T cell epitopes. Hypothesis: CRIM-positive IPD patients are tolerized to their own residual native GAA (nGAA) but may develop ATA to ERT with rhGAA. Using well-established computational tools to identify T cell epitopes in rhGAA which are predicted to stimulate CD4 T cells (and thus promote a T dependent B cell response to rhGAA), patients may be classified as high or low risk for the development of ATA. T cell epitopes that are cross-conserved between nGAA and rhGAA (and other endogenous epitopes) are unlikely to induce a T cell response. GAA-iTEM currently predicts ATA risk, using the patient’s HLA type and nGAA sequence. We propose to improve GAA-iTEM using newly accessible clinical data and samples. In Specific Aim 1, 40 CRIM+ IPD patients followed at Duke with defined ATA responses will be evaluated using GAA-iTEM to generate a patient-specific GAA-Individualized T cell Epitope Measure (GAA-iTEM) score. Clinical and genetic factors will be used to refine the predictive tool, which will be made available through a prototype graphical user interface to Duke clinicians, who will assess patient-specific risk and deposit clinical data for future calibration of the prediction algorithm. In Specific Aim 2, GAA CD4 T cell effector and regulatory epitopes identified in silico will be evaluated for HLA binding, cytokine stimulation, and generation of Tregs. Overall Impact: GAA-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 mutations, improving decision-making regarding ITI treatment. Once validated, the new GAA-iTEM would be used to assess ATA risk in a prospective study, and to develop ATA-risk assessment tools for related genetic disorders.

Public Health Relevance Statement:
PROJECT NARRATIVE Infantile Pompe Disease (IPD) is a glycogen storage disorder caused by a deficiency of acid alpha- glucosidase (GAA) that, without treatment, leads to death by cardiorespiratory failure within the first two years of life. The only treatment currently available is enzyme replacement with recombinant GAA, but many patients develop anti-therapeutic antibodies (ATA) that render the therapy ineffective. This 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 information, with 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.

Project Terms:
Adverse effects; Algorithms; Antibody Response; Antibody Therapy; Antibody titer measurement; Appearance; Assessment tool; B-Lymphocytes; base; Binding; Biological Assay; Bystander Suppression; Calibration; CD4 Positive T Lymphocytes; Cessation of life; Clinical; Clinical Data; clinical risk; cohort; Computer Simulation; computerized tools; cross reactivity; cytokine; Data Storage and Retrieval; Decision Making; Deposition; Development; Diagnostic; Disease; Effector Cell; enzyme replacement therapy; Enzymes; Epitopes; Evaluation; Failure; Future; Generations; Genetic; Genetic Diseases; genetic information; Glucan 1,4-alpha-Glucosidase; glucosidase; Glycogen; Glycogen storage disease type II; Goals; graphical user interface; Haplotypes; high risk; HLA-DRB1; Human; Immune; Immune Tolerance; immunogenicity; Immunologics; Immunosuppression; improved; In Vitro; Individual; individual patient; ineffective therapies; infancy; Infant; Informatics; Intuition; Life; Long-Term Effects; Lysosomes; Measures; Medical Genetics; Methods; Modeling; Mutation; Myocardium; Neoadjuvant Therapy; Online Systems; Other Genetics; Patient risk; Patients; Peptides; Periodicity; Peripheral Blood Mononuclear Cell; personalized approach; personalized predictions; Pharmaceutical Preparations; precision genetics; prediction algorithm; predictive tools; Predictive Value; Prevention; Prospective Studies; protein expression; Proteins; Protocols documentation; prototype; Quality of life; Recombinants; Regimen; Regulatory T-Lymphocyte; Research; Research Personnel; Residual state; response; Retrospective Studies; Risk; Risk Assessment; Sampling; Secure; Skeletal Muscle; Smooth Muscle; standard of care; Sustainable Development; T cell response; T-Lymphocyte Epitopes; Tetanus Toxoid; Therapeutic; Therapeutic antibodies; Time; tool; Treatment Efficacy; Universities; Validation

Significance: Infantile Pompe Disease (IPD) is an autosomal recessive glycogen storage disorder caused by a deficiency of acid alpha-glucosidase (GAA), leading to accumulation of glycogen in lysosomes, primarily in skeletal, cardiac and smooth muscles. Untreated IPD infants die within the first 2 years of life. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) improves survival and quality of life, but the development of sustained anti-therapeutic antibodies (ATA) potentially reduces ERT efficacy. All IPD patients who have no GAA protein expression (circulating cross-reactive immunologic material [CRIM]-negative) are predicted to mount high titer ATA, and are treated with an intensive Immune Tolerance Induction (ITI) regimen. While some CRIM-positive IPD patients become tolerized to ERT over time, over one-third of CRIM-positive patients still develop treatment-limiting ATA. There is currently no effective method for determining which CRIM-positive patients are at risk of developing treatment-limiting ATA, and would therefore benefit from treatment with an ITI regimen. This project will validate a recently developed algorithm, GAA-iTEM, for predicting the risk of ATA development for individual IPD patients, in a retrospective study of clinical data and in vitro studies of GAA T cell epitopes. Hypothesis: CRIM-positive IPD patients are tolerized to their own residual native GAA (nGAA) but may develop ATA to ERT with rhGAA. Using well-established computational tools to identify T cell epitopes in rhGAA which are predicted to stimulate CD4 T cells (and thus promote a T dependent B cell response to rhGAA), patients may be classified as high or low risk for the development of ATA. T cell epitopes that are cross-conserved between nGAA and rhGAA (and other endogenous epitopes) are unlikely to induce a T cell response. GAA-iTEM currently predicts ATA risk, using the patient’s HLA type and nGAA sequence. We propose to improve GAA-iTEM using newly accessible clinical data and samples. In Specific Aim 1, 40 CRIM+ IPD patients followed at Duke with defined ATA responses will be evaluated using GAA-iTEM to generate a patient-specific GAA-Individualized T cell Epitope Measure (GAA-iTEM) score. Clinical and genetic factors will be used to refine the predictive tool, which will be made available through a prototype graphical user interface to Duke clinicians, who will assess patient-specific risk and deposit clinical data for future calibration of the prediction algorithm. In Specific Aim 2, GAA CD4 T cell effector and regulatory epitopes identified in silico will be evaluated for HLA binding, cytokine stimulation, and generation of Tregs. Overall Impact: GAA-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 mutations, improving decision-making regarding ITI treatment. Once validated, the new GAA-iTEM would be used to assess ATA risk in a prospective study, and to develop ATA-risk assessment tools for related genetic disorders.

Public Health Relevance Statement:
PROJECT NARRATIVE Infantile Pompe Disease (IPD) is a glycogen storage disorder caused by a deficiency of acid alpha- glucosidase (GAA) that, without treatment, leads to death by cardiorespiratory failure within the first two years of life. The only treatment currently available is enzyme replacement with recombinant GAA, but many patients develop anti-therapeutic antibodies (ATA) that render the therapy ineffective. This 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 information, with 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.

NIH Spending Category:
Biotechnology; Chronic Liver Disease and Cirrhosis; Clinical Research; Digestive Diseases; Genetics; Immunization; Immunotherapy; Liver Disease; Orphan Drug; Precision Medicine; Rare Diseases

Project Terms:
Adverse effects; Algorithms; Antibody Response; Antibody Therapy; Antibody titer measurement; Appearance; Assessment tool; B-Lymphocytes; base; Binding; Biological Assay; Bystander Suppression; Calibration; CD4 Positive T Lymphocytes; Cessation of life; Clinical; Clinical Data; clinical risk; cohort; Computer Simulation; computerized tools; cross reactivity; cytokine; Data Storage and Retrieval; Decision Making; Deposition; Development; Diagnostic; Disease; effector T cell; enzyme replacement therapy; Enzymes; Epitopes; Evaluation; Failure; Future; Generations; Genetic; Genetic Diseases; genetic information; Glucan 1,4-alpha-Glucosidase; glucosidase; Glycogen; Glycogen storage disease type II; Goals; graphical user interface; Haplotypes; high risk; HLA-DRB1; Human; Immune; Immune Tolerance; immunogenicity; Immunologics; Immunosuppression; improved; In Vitro; Individual; individual patient; ineffective therapies; infancy; Infant; informatics tool; Intuition; Life; Long-Term Effects; Lysosomes; Measures; Medical Genetics; Methods; Modeling; Mutation; Myocardium; Neoadjuvant Therapy; Online Systems; Other Genetics; Patient risk; Patients; Peptides; Periodicity; Peripheral Blood Mononuclear Cell; personalized approach; personalized predictions; Pharmaceutical Preparations; precision genetics; prediction algorithm; predictive tools; Predictive Value; Prevention; Prospective Studies; protein expression; Proteins; Protocols documentation; prototype; Quality of life; Recombinants; Regimen; Regulatory T-Lymphocyte; Research; Research Personnel; Residual state; response; Retrospective Studies; Risk; Risk Assessment; Sampling; Secure; Skeletal Muscle; Smooth Muscle; standard of care; Sustainable Development; T cell response; T-Lymphocyte Epitopes; Tetanus Toxoid; Therapeutic; Therapeutic antibodies; Time; tool; Treatment Efficacy; Universities; Validation