Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA
Abstract Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accu...
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| Format: | Article |
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Springer Nature
2020-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911185 |
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| author | Helen Parker Stuart M Ellison Rebecca J Holley Claire O'Leary Aiyin Liao Jalal Asadi Emily Glover Arunabha Ghosh Simon Jones Fiona L Wilkinson David Brough Emmanuel Pinteaux Hervé Boutin Brian W Bigger |
| author_facet | Helen Parker Stuart M Ellison Rebecca J Holley Claire O'Leary Aiyin Liao Jalal Asadi Emily Glover Arunabha Ghosh Simon Jones Fiona L Wilkinson David Brough Emmanuel Pinteaux Hervé Boutin Brian W Bigger |
| author_sort | Helen Parker |
| collection | DOAJ |
| description | Abstract Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)‐1β and interleukin‐1 receptor antagonist (IL‐1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease‐specific 2‐O‐sulphated heparan sulphate was essential for priming an IL‐1β response via the Toll‐like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL‐1β secretion. IL‐1 blockade in mucopolysaccharidosis IIIA mice using IL‐1 receptor type 1 knockout or haematopoietic stem cell gene therapy over‐expressing IL‐1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL‐1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL‐1Ra as a potential neuronopathic lysosomal disease treatment. |
| format | Article |
| id | doaj-art-860e4ff997044c5bbd042e03d9871bf4 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-02-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-860e4ff997044c5bbd042e03d9871bf42025-08-20T04:02:56ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-02-0112311910.15252/emmm.201911185Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIAHelen Parker0Stuart M Ellison1Rebecca J Holley2Claire O'Leary3Aiyin Liao4Jalal Asadi5Emily Glover6Arunabha Ghosh7Simon Jones8Fiona L Wilkinson9David Brough10Emmanuel Pinteaux11Hervé Boutin12Brian W Bigger13Stem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterStem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterStem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterStem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterStem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterStem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterStem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterRoyal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation TrustRoyal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation TrustDivision of Biomedical Sciences, School of Healthcare Science, Manchester Metropolitan UniversityDivision of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterDivision of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterStem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of ManchesterAbstract Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)‐1β and interleukin‐1 receptor antagonist (IL‐1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease‐specific 2‐O‐sulphated heparan sulphate was essential for priming an IL‐1β response via the Toll‐like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL‐1β secretion. IL‐1 blockade in mucopolysaccharidosis IIIA mice using IL‐1 receptor type 1 knockout or haematopoietic stem cell gene therapy over‐expressing IL‐1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL‐1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL‐1Ra as a potential neuronopathic lysosomal disease treatment.https://doi.org/10.15252/emmm.201911185cognitive declinehaematopoietic stem cell gene therapyinflammasomeinterleukin‐1 receptor antagonistmucopolysaccharidosis |
| spellingShingle | Helen Parker Stuart M Ellison Rebecca J Holley Claire O'Leary Aiyin Liao Jalal Asadi Emily Glover Arunabha Ghosh Simon Jones Fiona L Wilkinson David Brough Emmanuel Pinteaux Hervé Boutin Brian W Bigger Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA EMBO Molecular Medicine cognitive decline haematopoietic stem cell gene therapy inflammasome interleukin‐1 receptor antagonist mucopolysaccharidosis |
| title | Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA |
| title_full | Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA |
| title_fullStr | Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA |
| title_full_unstemmed | Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA |
| title_short | Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA |
| title_sort | haematopoietic stem cell gene therapy with il 1ra rescues cognitive loss in mucopolysaccharidosis iiia |
| topic | cognitive decline haematopoietic stem cell gene therapy inflammasome interleukin‐1 receptor antagonist mucopolysaccharidosis |
| url | https://doi.org/10.15252/emmm.201911185 |
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