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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere11185
JournalEMBO Molecular Medicine
Issue number3
Early online date14 Feb 2020
Publication statusPublished - 6 Mar 2020


  • cognitive decline
  • haematopoietic stem cell gene therapy
  • inflammasome
  • interleukin-1 receptor antagonist
  • mucopolysaccharidosis


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