Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease
Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failur...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050120301509 |
| _version_ | 1818137736745320448 |
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| author | Giuseppa Piras Claudia Montiel-Equihua Yee-Ka Agnes Chan Slawomir Wantuch Daniel Stuckey Derek Burke Helen Prunty Rahul Phadke Darren Chambers Armando Partida-Gaytan Diego Leon-Rico Neelam Panchal Kathryn Whitmore Miguel Calero Sara Benedetti Giorgia Santilli Adrian J. Thrasher H. Bobby Gaspar |
| author_facet | Giuseppa Piras Claudia Montiel-Equihua Yee-Ka Agnes Chan Slawomir Wantuch Daniel Stuckey Derek Burke Helen Prunty Rahul Phadke Darren Chambers Armando Partida-Gaytan Diego Leon-Rico Neelam Panchal Kathryn Whitmore Miguel Calero Sara Benedetti Giorgia Santilli Adrian J. Thrasher H. Bobby Gaspar |
| author_sort | Giuseppa Piras |
| collection | DOAJ |
| description | Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failure within the first year of age in the more severe infantile forms. Currently available treatments have significant limitations and are not curative, highlighting a need for the development of alternative therapies. In this study, we investigated the use of a clinically relevant lentiviral vector to deliver systemically GAA through genetic modification of hematopoietic stem and progenitor cells (HSPCs). The overexpression of GAA in human HSPCs did not exert any toxic effect on this cell population, which conserved its stem cell capacity in xenograft experiments. In a murine model of Pompe disease treated at young age, we observed phenotypic correction of heart and muscle function with a significant reduction of glycogen accumulation in tissues after 6 months of treatment. These findings suggest that lentiviral-mediated HSPC gene therapy can be a safe alternative therapy for Pompe disease. |
| first_indexed | 2024-12-11T10:01:03Z |
| format | Article |
| id | doaj.art-228a291921bd422d9b985ca08e819866 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-11T10:01:03Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-228a291921bd422d9b985ca08e8198662022-12-22T01:12:07ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-09-0118558570Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe DiseaseGiuseppa Piras0Claudia Montiel-Equihua1Yee-Ka Agnes Chan2Slawomir Wantuch3Daniel Stuckey4Derek Burke5Helen Prunty6Rahul Phadke7Darren Chambers8Armando Partida-Gaytan9Diego Leon-Rico10Neelam Panchal11Kathryn Whitmore12Miguel Calero13Sara Benedetti14Giorgia Santilli15Adrian J. Thrasher16H. Bobby Gaspar17Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; Corresponding author: Giuseppa Piras, PhD, Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKCentre for Advanced Biomedical Imaging, University College London, London WC1E 6DD, UKEnzyme and Metabolic laboratory, Great Ormond Street Hospital, London WC1N 3JH, UKEnzyme and Metabolic laboratory, Great Ormond Street Hospital, London WC1N 3JH, UKDubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UKDubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInfection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK; Orchard Therapeutics Ltd., London EC4N 6EU, UK; Corresponding author: H. Bobby Gaspar, MD, PhD, Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failure within the first year of age in the more severe infantile forms. Currently available treatments have significant limitations and are not curative, highlighting a need for the development of alternative therapies. In this study, we investigated the use of a clinically relevant lentiviral vector to deliver systemically GAA through genetic modification of hematopoietic stem and progenitor cells (HSPCs). The overexpression of GAA in human HSPCs did not exert any toxic effect on this cell population, which conserved its stem cell capacity in xenograft experiments. In a murine model of Pompe disease treated at young age, we observed phenotypic correction of heart and muscle function with a significant reduction of glycogen accumulation in tissues after 6 months of treatment. These findings suggest that lentiviral-mediated HSPC gene therapy can be a safe alternative therapy for Pompe disease.http://www.sciencedirect.com/science/article/pii/S2329050120301509Pompe diseasehematopoietic stem cell gene therapylentiviral vectoracid alpha-glucosidaseGAAerythroid-specific enhancer |
| spellingShingle | Giuseppa Piras Claudia Montiel-Equihua Yee-Ka Agnes Chan Slawomir Wantuch Daniel Stuckey Derek Burke Helen Prunty Rahul Phadke Darren Chambers Armando Partida-Gaytan Diego Leon-Rico Neelam Panchal Kathryn Whitmore Miguel Calero Sara Benedetti Giorgia Santilli Adrian J. Thrasher H. Bobby Gaspar Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease Molecular Therapy: Methods & Clinical Development Pompe disease hematopoietic stem cell gene therapy lentiviral vector acid alpha-glucosidase GAA erythroid-specific enhancer |
| title | Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease |
| title_full | Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease |
| title_fullStr | Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease |
| title_full_unstemmed | Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease |
| title_short | Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease |
| title_sort | lentiviral hematopoietic stem cell gene therapy rescues clinical phenotypes in a murine model of pompe disease |
| topic | Pompe disease hematopoietic stem cell gene therapy lentiviral vector acid alpha-glucosidase GAA erythroid-specific enhancer |
| url | http://www.sciencedirect.com/science/article/pii/S2329050120301509 |
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