Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy
IntroductionPompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant...
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1336599/full |
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| author | Hui-An Chen Hui-An Chen Hui-An Chen Rai-Hseng Hsu Rai-Hseng Hsu Rai-Hseng Hsu Ching-Ya Fang Ankit K. Desai Ni-Chung Lee Ni-Chung Lee Ni-Chung Lee Wuh-Liang Hwu Wuh-Liang Hwu Wuh-Liang Hwu Fuu-Jen Tsai Priya S. Kishnani Yin-Hsiu Chien Yin-Hsiu Chien Yin-Hsiu Chien |
| author_facet | Hui-An Chen Hui-An Chen Hui-An Chen Rai-Hseng Hsu Rai-Hseng Hsu Rai-Hseng Hsu Ching-Ya Fang Ankit K. Desai Ni-Chung Lee Ni-Chung Lee Ni-Chung Lee Wuh-Liang Hwu Wuh-Liang Hwu Wuh-Liang Hwu Fuu-Jen Tsai Priya S. Kishnani Yin-Hsiu Chien Yin-Hsiu Chien Yin-Hsiu Chien |
| author_sort | Hui-An Chen |
| collection | DOAJ |
| description | IntroductionPompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels.MethodIn a single-center, open-label prospective study, we assessed ITI therapy’s efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI.ResultsThis study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea.ConclusionITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172. |
| first_indexed | 2024-04-24T06:38:08Z |
| format | Article |
| id | doaj.art-d580f3c7d33d45768fcfbe1d68b78034 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-24T06:38:08Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-d580f3c7d33d45768fcfbe1d68b780342024-04-23T04:26:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-04-011510.3389/fimmu.2024.13365991336599Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapyHui-An Chen0Hui-An Chen1Hui-An Chen2Rai-Hseng Hsu3Rai-Hseng Hsu4Rai-Hseng Hsu5Ching-Ya Fang6Ankit K. Desai7Ni-Chung Lee8Ni-Chung Lee9Ni-Chung Lee10Wuh-Liang Hwu11Wuh-Liang Hwu12Wuh-Liang Hwu13Fuu-Jen Tsai14Priya S. Kishnani15Yin-Hsiu Chien16Yin-Hsiu Chien17Yin-Hsiu Chien18Department of Medical Genetics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University College of Medicine, Taipei, TaiwanDepartment of Medical Genetics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University College of Medicine, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, Taipei, TaiwanDivision of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United StatesDepartment of Medical Genetics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University College of Medicine, Taipei, TaiwanDepartment of Medical Genetics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, Taipei, TaiwanCenter for Precision Medicine, China Medical University Hospital, Taichung, TaiwanDepartment of Medical Research, China Medical University Hospital, Taichung, TaiwanDivision of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United StatesDepartment of Medical Genetics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University Hospital, Taipei, TaiwanDepartment of Pediatrics, National Taiwan University College of Medicine, Taipei, TaiwanIntroductionPompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels.MethodIn a single-center, open-label prospective study, we assessed ITI therapy’s efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI.ResultsThis study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea.ConclusionITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1336599/fullPompe diseaseenzyme replacement therapyalglucosidase alfaimmunomodulation therapyanti-drug antibody |
| spellingShingle | Hui-An Chen Hui-An Chen Hui-An Chen Rai-Hseng Hsu Rai-Hseng Hsu Rai-Hseng Hsu Ching-Ya Fang Ankit K. Desai Ni-Chung Lee Ni-Chung Lee Ni-Chung Lee Wuh-Liang Hwu Wuh-Liang Hwu Wuh-Liang Hwu Fuu-Jen Tsai Priya S. Kishnani Yin-Hsiu Chien Yin-Hsiu Chien Yin-Hsiu Chien Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy Frontiers in Immunology Pompe disease enzyme replacement therapy alglucosidase alfa immunomodulation therapy anti-drug antibody |
| title | Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy |
| title_full | Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy |
| title_fullStr | Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy |
| title_full_unstemmed | Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy |
| title_short | Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy |
| title_sort | optimizing treatment outcomes immune tolerance induction in pompe disease patients undergoing enzyme replacement therapy |
| topic | Pompe disease enzyme replacement therapy alglucosidase alfa immunomodulation therapy anti-drug antibody |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1336599/full |
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