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

EMBO Mol Med. 2020 Mar 6;12(3):e11185. doi: 10.15252/emmm.201911185. Epub 2020 Feb 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amyloid beta-Peptides
  • Animals
  • Child
  • Child, Preschool
  • Cognition*
  • Female
  • Genetic Therapy*
  • Hematopoietic Stem Cells*
  • Humans
  • Inflammasomes / metabolism
  • Interleukin 1 Receptor Antagonist Protein* / genetics
  • Interleukin-1beta / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mucopolysaccharidosis III / therapy*


  • Amyloid beta-Peptides
  • Inflammasomes
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta