Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIACitation formats

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Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA. / Parker, Helen; Ellison, Stuart M; Holley, Rebecca J; O'Leary, Claire; Liao, Aiyin; Asadi, Jalal; Glover, Emily; Ghosh, Arunabha; Jones, Simon; Wilkinson, Fiona L; Brough, David; Pinteaux, Emmanuel; Boutin, Hervé; Bigger, Brian W.

In: EMBO Molecular Medicine, Vol. 12, No. 3, e11185, 06.03.2020.

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Parker, Helen ; Ellison, Stuart M ; Holley, Rebecca J ; O'Leary, Claire ; Liao, Aiyin ; Asadi, Jalal ; Glover, Emily ; Ghosh, Arunabha ; Jones, Simon ; Wilkinson, Fiona L ; Brough, David ; Pinteaux, Emmanuel ; Boutin, Hervé ; Bigger, Brian W. / Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA. In: EMBO Molecular Medicine. 2020 ; Vol. 12, No. 3.

Bibtex

@article{9b76d7895ed5490e83ae7c8d2cd93b57,
title = "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 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.",
keywords = "cognitive decline, haematopoietic stem cell gene therapy, inflammasome, interleukin-1 receptor antagonist, mucopolysaccharidosis",
author = "Helen Parker and Ellison, {Stuart M} and Holley, {Rebecca J} and Claire O'Leary and Aiyin Liao and Jalal Asadi and Emily Glover and Arunabha Ghosh and Simon Jones and Wilkinson, {Fiona L} and David Brough and Emmanuel Pinteaux and Herv{\'e} Boutin and Bigger, {Brian W}",
note = "{\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2020",
month = mar,
day = "6",
doi = "10.15252/emmm.201911185",
language = "English",
volume = "12",
journal = "EMBO Molecular Medicine ",
issn = "1757-4676",
publisher = "John Wiley & Sons Ltd",
number = "3",

}

RIS

TY - JOUR

T1 - Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA

AU - Parker, Helen

AU - Ellison, Stuart M

AU - Holley, Rebecca J

AU - O'Leary, Claire

AU - Liao, Aiyin

AU - Asadi, Jalal

AU - Glover, Emily

AU - Ghosh, Arunabha

AU - Jones, Simon

AU - Wilkinson, Fiona L

AU - Brough, David

AU - Pinteaux, Emmanuel

AU - Boutin, Hervé

AU - Bigger, Brian W

N1 - © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2020/3/6

Y1 - 2020/3/6

N2 - 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.

AB - 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.

KW - cognitive decline

KW - haematopoietic stem cell gene therapy

KW - inflammasome

KW - interleukin-1 receptor antagonist

KW - mucopolysaccharidosis

U2 - 10.15252/emmm.201911185

DO - 10.15252/emmm.201911185

M3 - Article

C2 - 32057196

VL - 12

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

SN - 1757-4676

IS - 3

M1 - e11185

ER -