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. 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. Our goal is to investigate the safety and efficacy of gene transfer treatment as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant(s) from a parent. In our now closed earlier protocol that provided background to the current lentivector protocol, we used gamma-retroviral vector to mediate the gene transfer without any conditioning regimen, which did not achieve sustained correction and expansion of the genetically corrected lymphoid cells. The first two subjects of that earlier trial, later undertook a matched, unrelated stem cell transplant 4 and 2 years ago respectively, and both are well clinically, with good levels of stable donor cell engraftment. In this past year, we have initiated a new protocol to treat similar older subjects with partially corrected X-SCID using a lentivector mediated gene transfer combined with mild/moderate dose of busulfan 6mg/kg total for myeloconditioning. This vector is developed in collaboration with investigators (Dr Brian Sorrentino and Dr John Gray) at St Jude Children's Research Hospital, Memphis. To date we have treated 2 subjects who tolerated the conditioning well and no serious adverse events have been observed. The level of gene correction in myeloid cells appears stable in the range of 10-17% at 3 and 9 months, respectively after gene therapy, and marking in T and B cells is increasing as would be expected from the selective growth and suvival advantage that accrues from the gene therapy in XSCID lymphocytes. No adverse events have been observed, and gene marking appears polyclonal. Formal assessment for clinical benefit from the therapy will be performed at two years after treatment.

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