This project investigates diagnosis and treatment of severe combined immunodeficiency. Affected infants have severe infections that are fatal unless the immune system can be restored. Bone marrow transplant (BMT) is life-saving if the disease is detected in time. SCID is most often caused by defects in the X-linked IL2RG gene which encodes the common gamma chain of receptors for cytokines. When this gene is defective, lymphocytes do not develop normally. To know how mutations in the IL2RG gene cause X-linked SCID (XSCID), we collect samples of blood or tissue, perform DNA analysis, assess expression of common gamma chain protein, and analyze its function. Mutations occur in all exons of the gene. Unusual mutations give clues to how the gene normally interacts with other proteins on the surface of the cell and in the cytoplasm of the cell. Certain mutations permit residual function and have distinct clinical characteristics. We look for other gene defects in patients with SCID but with no mutation in the IL2RG. We perform carrier testing, genetic counseling prenatal diagnosis, making affected infants eligible for improved early treatments. Despite improved survival with BMT, many XSCID patients are not completely cured, raising the question whether retroviral gene transfer ex vivo to autologous blood-forming cells could improve outcome. We have a complete XSCID gene therapy program, including vector development, animal models, retroviral transduction optimization, clinical evaluation of patients who have failed standard BMT treatment, and a clinical gene therapy protocol under which 2 patients have been treated. In a French gene therapy trial for XSCID, 8 patients had immune reconstitution, but 2 developed leukemia due to gene therapy vector insertion near an oncogene. Our trial is to treat only patients who have failed standard bone marrow transplant treatment. 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 applicable to further human diseases such as additional SCID due to non-X-linked genes and HIV/AIDS. The true incidence of SCID is unknown because affected infants may die of infections without being diagnosed. Early identification by population-based newborn screening would enable more infants to be saved and would determine the true disease incidence. We have developed a newborn screening test for SCID of any genotype by quantitation of TRECs (T cell receptor excision circels). The test has been validated on blood spots from the Maryland State newborn screening program.
| Chan, Kee; Puck, Jennifer M (2005) Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol 115:391-8 |
| Chinen, Javier; Puck, Jennifer M (2004) Perspectives of gene therapy for primary immunodeficiencies. Curr Opin Allergy Clin Immunol 4:523-7 |
| Chinen, Javier; Puck, Jennifer M (2004) Successes and risks of gene therapy in primary immunodeficiencies. J Allergy Clin Immunol 113:595-603; quiz 604 |
| Hale, Laura P; Buckley, Rebecca H; Puck, Jennifer M et al. (2004) Abnormal development of thymic dendritic and epithelial cells in human X-linked severe combined immunodeficiency. Clin Immunol 110:63-70 |
| Notarangelo, Luigi; Casanova, Jean-Laurent; Fischer, Alain et al. (2004) Primary immunodeficiency diseases: an update. J Allergy Clin Immunol 114:677-87 |
| Matsuzaki, Hajime; Loi, Halina; Dong, Shoulian et al. (2004) Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res 14:414-25 |
| Cooper, Max D; Lanier, Lewis L; Conley, Mary Ellen et al. (2003) Immunodeficiency disorders. Hematology Am Soc Hematol Educ Program :314-30 |
| 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 |
| Vihinen, M; Arredondo-Vega, F X; Casanova, J L et al. (2001) Primary immunodeficiency mutation databases. Adv Genet 43:103-88 |
| Fanos, J H; Davis, J; Puck, J M (2001) Sib understanding of genetics and attitudes toward carrier testing for X-linked severe combined immunodeficiency. Am J Med Genet 98:46-56 |
Showing the most recent 10 out of 11 publications
