The long-term goal of the proposed research is to test the feasibility of two novel therapies, enzyme therapy and gene therapy, in the treatment of inherited or acquired diseases. Adenosine deaminase (ADA) deficiency is a genetic disease that has been the major testing ground for the therapeutic efficacy of these treatments. ADA is a purine catabolic enzyme that is required for the development for the immune system. A genetic deficiency in ADA is associated with severe combined immunodeficiency (SCID). ADA deficiency has had considerable impact in the development of novel therapy in several areas of medicine. The initial discovery that some forms of SCID results from ADA deficiency led to the successful use of certain ADA inhibitor and cytotoxic purine nucleoside analogs to treat lymphocytic leukemias. More recently, ADA deficiency has become the testing ground for novel therapies, especially enzyme therapy and gene therapy. Although the initial results of these therapeutic approaches are encouraging, inconsistent outcomes have raised numerous important questions regarding; these treatments protocols. In particular, the parameters and clinical variables that influence therapeutic success are not well understood. The principal investigator believes that the pace with which these new therapies can be tested and refined can be increased dramatically with the use of the genetically engineered ADA-deficient mice recently created in his laboratory. These mice retain most features relative to ADA deficiency in humans and should serve as a model system to test various aspects of enzyme therapy and gene therapy. The long range goals of the proposed research are to identify parameters affecting the success of enzyme therapy and gene therapy in the treatment of ADA deficiency. Proposed studies should have relevance to a large number of metabolic and molecular diseases where enzyme therapy would be applicable.
| Aldrich, Melissa B; Chen, Wilma; Blackburn, Michael R et al. (2003) Impaired germinal center maturation in adenosine deaminase deficiency. J Immunol 171:5562-70 |
| Apasov, S G; Blackburn, M R; Kellems, R E et al. (2001) Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest 108:131-41 |
| Aldrich, M B; Blackburn, M R; Kellems, R E (2000) The importance of adenosine deaminase for lymphocyte development and function. Biochem Biophys Res Commun 272:311-5 |
| Aldrich, M B; Blackburn, M R; Datta, S K et al. (2000) Adenosine deaminase-deficient mice: models for the study of lymphocyte development and adenosine signaling. Adv Exp Med Biol 486:57-63 |
