Defects in the gamma chain gene of the IL-2 receptor (IL2RG) cause X- linked severe combined immunodeficiency (XSCID). The only current lifesaving treatment is bone marrow transplantation, but drawbacks of this include the lack of HLA matched related donors, poor post- transplant B cell function and graft vs. host disease. An in vivo growth advantage for cells with intact IL2RG makes XSCID a promising disease for retroviral gene therapy delivered to autologous bone marrow stem cells. We have made and compared different retroviruses for titer and gamma chain expression and derived two acceptable constructs for preclinical and clinical studies. Longterm expression of transduced human gamma chain protein was achieved in a dog model. Normal humans treated with cytokines mobilize hematopoietic stem cells, which are usually rare and poorly able to accept a retrovirus. We are treating XSCID patients with the cytokine G-CSF to test whether mobilization of stem cells will occur. The stem cells are currently being used for research to define the best gene transfer conditions. Once optimal gene transfer conditions are devised and clinical grade vectors are made and approved, gene therapy trials will be planned in XSCID patients who have responded suboptimally to conventional bone marrow transplantation therapy. - Gene Therapy, Genetics, Clinical Research, Pediatric Research, Immunology, Infectious Diseases, Bone Marrow, Stem Cell Research - Human Subjects
| Myers, Laurie A; Patel, Dhavalkumar D; Puck, Jennifer M et al. (2002) Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood 99:872-8 |
| Licht, Thomas; Haskins, Mark; Henthorn, Paula et al. (2002) Drug selection with paclitaxel restores expression of linked IL-2 receptor gamma -chain and multidrug resistance (MDR1) transgenes in canine bone marrow. Proc Natl Acad Sci U S A 99:3123-8 |
| Tsai, Emily J; Malech, Harry L; Kirby, Martha R et al. (2002) Retroviral transduction of IL2RG into CD34(+) cells from X-linked severe combined immunodeficiency patients permits human T- and B-cell development in sheep chimeras. Blood 100:72-9 |
| Vihinen, M; Arredondo-Vega, F X; Casanova, J L et al. (2001) Primary immunodeficiency mutation databases. Adv Genet 43:103-88 |
