TY - JOUR
T1 - Targeting a Pre-existing Anti-transgene T Cell Response for Effective Gene Therapy of MPS-I in the Mouse Model of the Disease
T2 - Molecular Therapy
AU - Squeri, G
AU - Passerini, L
AU - Ferro, F
AU - Laudisa, C
AU - Tomasoni, D
AU - Deodato, F
AU - Donati, MA
AU - Gasperini, S
AU - Aiuti, A
AU - Bernardo, ME
AU - Gentner, B
AU - Naldini, L
AU - Annoni, A
AU - Biffi, A
AU - Gregori, S
PY - 2019
Y1 - 2019
N2 - 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. MPS-I patients receiving enzyme replacement therapy develop an anti-IDUA immune response that may affect ex vivo gene therapy. Squeri et al. show, in the MPS-I murine model, that pre-existing IDUA-specific CD8 + T cell response impairs LV-transduced HSC engraftment and that the efficacy of ex vivo gene therapy is rescued by lympho-depleting drugs. © 2019 The Authors
AB - 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. MPS-I patients receiving enzyme replacement therapy develop an anti-IDUA immune response that may affect ex vivo gene therapy. Squeri et al. show, in the MPS-I murine model, that pre-existing IDUA-specific CD8 + T cell response impairs LV-transduced HSC engraftment and that the efficacy of ex vivo gene therapy is rescued by lympho-depleting drugs. © 2019 The Authors
U2 - 10.1016/j.ymthe.2019.04.014
DO - 10.1016/j.ymthe.2019.04.014
M3 - Article
VL - 27
SP - 1215
EP - 1227
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 7
ER -