This program is designed to develop and test methods for gene therapy to correct diseases of the immune system. The test disease will be the most common form (the X-linked form) of severe combined immunodeficiency (SCID), or 'Bubble Boy' disease. Bone marrow transplantation for SCID, while rescuing many patients, sometimes does not provide complete correction of the immune system. Gene therapy may be another option. Gene therapy could also be useful for other immune conditions, including HIV. We have now developed retroviral vectors to carry a correct copy of the X-linked SCID gene IL2RG (interleukin-2 receptor gamma chain, or common gamma chain) into cells from patients with defects in this gene. The genes are transferred bone marrow stem cells, which are self-renewing for the lifetime of a person and can differentiate as needed into all the different types of blood cells. We have proven that we can obtain these stem cells from peripheral blood by giving patients injections of the cytokine G-CSF. After testing several vectors we found one with the best gene expression and ability to enter human blood-forming stem cells. We have tested and will continue to test 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 shown that it is likely we could help humans with X-linked SCID by doing gene therapy. The first gene therapy for X-linked SCID was done a few years ago in France. Our plan is different from this one because in France, infants who had not been treated already were given gene therapy as their only treatment. While most of the children in the French trial had great benefit, 2 of the 10 infants developed leukemia due to the gene therapy vector inserting itself near an oncogene. Our trial will treat only patients who have already had the standard bone marrow transplant treatment, but have failed to get acceptable immune function. Our clinical trial for gene therapy for humans with X-linked SCID will be conducted at NIH in collaboration with Dr. Harry Malech of NIAID. We will enroll patients for whom bone marrow transplant, the standard treatment, has failed at least twice. SCID is only one of many diseases that could be approached by gene therapy to blood-forming stem cells. Our studies with gene transfer for treating SCID are a pilot application chosen because of the special biology of the IL2RG gene. This gene confers a selective advantage on corrected cells as compared to cells without a functioning gene. Therefore if gene therapy is successful in SCID, the methods will be used for development of more general human gene transfer protocols that may be beneficial for patients with other diseases such as additional SCID diseases due to non-X-linked genes and 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 |
