This project involves the conduct of a therapeutic clinical trial using autologous blood stem cell targeted gene therapy to treat X-linked severe combined immune deficiency. Retroviral gene therapy can restore immunity to infants with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (gc) of receptors for interleukins (IL)-2, -4, -7, -9, -15 and -21. We investigated the safety and efficacy of gene therapy as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant(s) from a parent. Subjects received retrovirus transduced autologous peripherally mobilized CD34+ hematopoietic cells. Initial multi-lineage retroviral marking and improvements in health occurred in all 3 children, and T cell function significantly improved in the youngest subject (age 10 years). In year 2009, all patients are at long term follow up stage. Long term benefit continues only in the youngest patient. The first treated patient undertook a matched, unrelated transplant successfully, while the second patient has stable low level of marking in his T lymphocytes. Further follow-up of clinical, immunologic and molecular parameters in these treated patients is critical for establishing the long-term safety and efficacy of this approach to gene therapy for pre-adolescents with XSCID who have failed to achieve or maintain immune reconstitution after BMT. In collaboration with investigators at St. Jude Children's Research Hospital, led by Brian Sorrentino at that institution, we are actively developing the vectors and procedures to embark on a clinical trial of gene therapy for X-SCID using a novel self-inactivating, insulated lentivector with short EF-1a mammalian internal promotor. Protocols have been written and presented and approved by the NIH Recombinant Advisory Committee. IRB review is anticipated in the near future and additional safety studies are in progress to satisfy requirements of the FDA to achieve IND approval.
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