Open AccessHaematopoietic stem cell gene therapy with IL ‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA
Author(s) -
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
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911185
Subject(s) - stem cell , regenerative medicine , stem cell biology , medicine , biology , genetics , gene , reproductive technology , embryogenesis
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 NLRP 3 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.