Targeting a Pre-existing Anti-transgene T Cell Response for Effective Gene Therapy of MPS-I in the Mouse Model of the Disease

Mol Ther. 2019 Jul 3;27(7):1215-1227. doi: 10.1016/j.ymthe.2019.04.014. Epub 2019 Apr 19.


Mucopolysaccharidosis type I (MPS-I) is a severe genetic disease caused by a deficiency of the alpha-L-iduronidase (IDUA) enzyme. Ex vivo hematopoietic stem cell (HSC) gene therapy is a promising therapeutic approach for MPS-I, as demonstrated by preclinical studies performed in naive MPS-I mice. However, after enzyme replacement therapy (ERT), several MPS-I patients develop anti-IDUA immunity that may jeopardize ex vivo gene therapy efficacy. Here we treat MPS-I mice with an artificial immunization protocol to mimic the ERT effect in patients, and we demonstrate that IDUA-corrected HSC engraftment is impaired in pre-immunized animals by IDUA-specific CD8+ T cells spared by pre-transplant irradiation. Conversely, humoral anti-IDUA immunity does not impact on IDUA-corrected HSC engraftment. The inclusion of lympho-depleting agents in pre-transplant conditioning of pre-immunized hosts allowes rescue of IDUA-corrected HSC engraftment, which is proportional to CD8+ T cell eradication. Overall, these data demonstrate the relevance of pre-existing anti-transgene T cell immunity on ex vivo HSC gene therapy, and they suggest the application of tailored immune-depleting treatments, as well as a deeper immunological characterization of patients, to safeguard the therapeutic effects of ex vivo HSC gene therapy in immunocompetent hosts.

Keywords: ERT; HSC; MPS-I; depleting agents; fludarabine; gene therapy; immune response; lentiviral vector; pre-existing immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Replacement Therapy / adverse effects
  • Gene Knockout Techniques
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Hematopoietic Stem Cell Transplantation / methods*
  • Humans
  • Iduronidase / genetics
  • Iduronidase / immunology
  • Immunity, Cellular / drug effects
  • Immunization / methods
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mucopolysaccharidosis I / therapy*
  • Spleen / pathology
  • Transgenes / immunology*


  • Antibodies, Monoclonal
  • Immunoglobulin G
  • Iduronidase