Lentiviral Hematopoietic Stem Cell Gene Therapy Rescues Clinical Phenotypes in a Murine Model of Pompe Disease.

Autor:	Piras G; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Montiel-Equihua C; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Chan YA; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Wantuch S; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Stuckey D; Centre for Advanced Biomedical Imaging, University College London, London WC1E 6DD, UK., Burke D; Enzyme and Metabolic laboratory, Great Ormond Street Hospital, London WC1N 3JH, UK., Prunty H; Enzyme and Metabolic laboratory, Great Ormond Street Hospital, London WC1N 3JH, UK., Phadke R; Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK., Chambers D; Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK., Partida-Gaytan A; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Leon-Rico D; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Panchal N; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Whitmore K; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Calero M; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Benedetti S; Infection, 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, UK., Santilli G; Infection, 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, UK., Thrasher AJ; Infection, Immunity and Inflammation Program, Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK., Gaspar HB; Infection, 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.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2020 Jul 06; Vol. 18, pp. 558-570. Date of Electronic Publication: 2020 Jul 06 (Print Publication: 2020).
DOI:	10.1016/j.omtm.2020.07.001
Abstrakt:	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. (© 2020 The Authors.)
Databáze:	MEDLINE
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