Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease
Abstract Pompe disease is a metabolic myopathy due to acid alpha‐glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-10-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114434 |
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| author | Antonietta Tarallo Carla Damiano Sandra Strollo Nadia Minopoli Alessia Indrieri Elena Polishchuk Francesca Zappa Edoardo Nusco Simona Fecarotta Caterina Porto Marcella Coletta Roberta Iacono Marco Moracci Roman Polishchuk Diego Luis Medina Paola Imbimbo Daria Maria Monti Maria Antonietta De Matteis Giancarlo Parenti |
| author_facet | Antonietta Tarallo Carla Damiano Sandra Strollo Nadia Minopoli Alessia Indrieri Elena Polishchuk Francesca Zappa Edoardo Nusco Simona Fecarotta Caterina Porto Marcella Coletta Roberta Iacono Marco Moracci Roman Polishchuk Diego Luis Medina Paola Imbimbo Daria Maria Monti Maria Antonietta De Matteis Giancarlo Parenti |
| author_sort | Antonietta Tarallo |
| collection | DOAJ |
| description | Abstract Pompe disease is a metabolic myopathy due to acid alpha‐glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha‐glucosidase (rhGAA), currently the standard of care for Pompe disease patients, and whether correction of oxidative stress may be beneficial for rhGAA therapy. We found elevated oxidative stress levels in tissues from the Pompe disease murine model and in patients’ cells. In cells, stress levels inversely correlated with the ability of rhGAA to correct the enzymatic deficiency. Antioxidants (N‐acetylcysteine, idebenone, resveratrol, edaravone) improved alpha‐glucosidase activity in rhGAA‐treated cells, enhanced enzyme processing, and improved mannose‐6‐phosphate receptor localization. When co‐administered with rhGAA, antioxidants improved alpha‐glucosidase activity in tissues from the Pompe disease mouse model. These results indicate that oxidative stress impacts on the efficacy of enzyme replacement therapy in Pompe disease and that manipulation of secondary abnormalities may represent a strategy to improve the efficacy of therapies for this disorder. |
| format | Article |
| id | doaj-art-c9d76b1dfda5478da27f60239b67fa37 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-c9d76b1dfda5478da27f60239b67fa372025-08-20T04:03:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-10-01131112110.15252/emmm.202114434Correction of oxidative stress enhances enzyme replacement therapy in Pompe diseaseAntonietta Tarallo0Carla Damiano1Sandra Strollo2Nadia Minopoli3Alessia Indrieri4Elena Polishchuk5Francesca Zappa6Edoardo Nusco7Simona Fecarotta8Caterina Porto9Marcella Coletta10Roberta Iacono11Marco Moracci12Roman Polishchuk13Diego Luis Medina14Paola Imbimbo15Daria Maria Monti16Maria Antonietta De Matteis17Giancarlo Parenti18Telethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineDepartment of Translational Medical Sciences, Federico II UniversityDepartment of Translational Medical Sciences, Federico II UniversityDepartment of Translational Medical Sciences, Federico II UniversityDepartment of Biology, University of Naples "Federico II", Complesso Universitario di Monte S. AngeloDepartment of Biology, University of Naples "Federico II", Complesso Universitario di Monte S. AngeloTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineDepartment of Chemical Sciences, Federico II UniversityDepartment of Chemical Sciences, Federico II UniversityTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineAbstract Pompe disease is a metabolic myopathy due to acid alpha‐glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha‐glucosidase (rhGAA), currently the standard of care for Pompe disease patients, and whether correction of oxidative stress may be beneficial for rhGAA therapy. We found elevated oxidative stress levels in tissues from the Pompe disease murine model and in patients’ cells. In cells, stress levels inversely correlated with the ability of rhGAA to correct the enzymatic deficiency. Antioxidants (N‐acetylcysteine, idebenone, resveratrol, edaravone) improved alpha‐glucosidase activity in rhGAA‐treated cells, enhanced enzyme processing, and improved mannose‐6‐phosphate receptor localization. When co‐administered with rhGAA, antioxidants improved alpha‐glucosidase activity in tissues from the Pompe disease mouse model. These results indicate that oxidative stress impacts on the efficacy of enzyme replacement therapy in Pompe disease and that manipulation of secondary abnormalities may represent a strategy to improve the efficacy of therapies for this disorder.https://doi.org/10.15252/emmm.202114434alpha‐glucosidaseenzyme replacement therapyN‐acetylcysteineoxidative stressPompe disease |
| spellingShingle | Antonietta Tarallo Carla Damiano Sandra Strollo Nadia Minopoli Alessia Indrieri Elena Polishchuk Francesca Zappa Edoardo Nusco Simona Fecarotta Caterina Porto Marcella Coletta Roberta Iacono Marco Moracci Roman Polishchuk Diego Luis Medina Paola Imbimbo Daria Maria Monti Maria Antonietta De Matteis Giancarlo Parenti Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease EMBO Molecular Medicine alpha‐glucosidase enzyme replacement therapy N‐acetylcysteine oxidative stress Pompe disease |
| title | Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease |
| title_full | Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease |
| title_fullStr | Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease |
| title_full_unstemmed | Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease |
| title_short | Correction of oxidative stress enhances enzyme replacement therapy in Pompe disease |
| title_sort | correction of oxidative stress enhances enzyme replacement therapy in pompe disease |
| topic | alpha‐glucosidase enzyme replacement therapy N‐acetylcysteine oxidative stress Pompe disease |
| url | https://doi.org/10.15252/emmm.202114434 |
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