This program is designed to develop and test methods for correcting the genetic defect in the most common form (the X-linked form) of severe combined immunodeficiency (SCID), the 'Boy in the Bubble' disease. Bone marrow transplantation, while rescuing many patinets, does not provide complete correction of the immune system in many cases of X-linked SCID. We are developing retroviral vectors to carry a correct copy of the gene IL2RG (interleukin-2 receptor gamma chain, or common gamma chain) into cells from patients with SCID due to defects in this gene. The genes are transferred to cell lines from affected patients and to their bone marrow stem cells, which are cells that are self-renewing and can differentiate into all the different types of blood cells. We are studying how to obtain these stem cells from peripheral blood by giving patients injections of the cytokine G-CSF. We have made and tested several vectors to find those with the best gene expression and rates of correction of human stem cells. We have tested these vectors in mice and human/sheep chimeras in which human stem cells grow into human blood cells that can be recovered from sheep. These studies have made possible the design of a clinical trial for gene therapy for humans with X-linked SCID, which is being conducted at NIH in collaboration with NIAID. We will enroll patients for whom bone marrow transplant, the standard treatment, has failed or not worked completely. Our studies with gene transfer for treating SCID will also help other applications of gene transfer to stem cells to treat immunodeficient conditions. In particular, these studies will use XSCID as a pilot disease for development of human gene transfer protocols that may be beneficial for patients with HIV/AIDS.
| 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 |
