Bone marrow or stem cell transplantation
Mucopolysaccharidosis type-I (MPS-I) is caused by the deficiency of alpha-L-iduronidase (IDUA) that results in glycosaminoglycan accumulation in tissues. The available treatments are enzyme-replacement therapy (ERT) and allogeneic hematopoietic stem cell (HSC) transplantation. An alternative therapeutic option is ex vivo hematopoietic stem cell (HSC) gene therapy and preclinical studies performed in mice demonstrated the efficacy of this approach based on lentiviral vectors in the absence of pre-existing anti-IDUA immunity. However, several MPS-I patients develop anti-IDUA immunity after enzyme replacement therapy (ERT), thus pre-existing immune response may jeopardize ex vivo HSC gene therapy efficacy. To study the impact of pre-existing anti-IDUA immunity on gene corrected HSC engraftment in enzyme pre-treated and immunized mice, we optimize an artificial immunization protocol in MPS-I mice to mimic the effect of ERT in patients. We demonstrate that engraftment of IDUA-corrected HSCs is impaired in pre-immunized MPS-I mice and that the rejection of transplanted cells is mediated by IDUA-specific CD8+ T cells. The selective depletion of IDUA-specific CD8+ T cells allows engraftment of IDUA-corrected HSCs in immunized MPS-I mice. Overall, these data demonstrate, for the first time, the relevance of pre-existing anti-transgene immunity on ex vivo HSC gene therapy and 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 immune-competent hosts.