Human X-linked agammaglobulinemia (XLA) is a severe immunodeficiency caused by a failure to develop sufficient numbers of B lymphocytes in the bone marrow of affected males. Alterations in function have been noted for those few B cells which are produced from the marrow. This results in a drastic reduction in serum immunoglobulin and a lack of functional antibody responses. The specific defect in XLA has been identified as a failure to produce sufficient levels of a cytoplasmic tyrosine kinase called BTK. A variety of mutations that act through different mechanisms to reduce the dosage of functional kinase have been defined. Definitive genetic therapy of this disease by expression of a wild type form of the enzyme in stem or B lineage progenitor cells would be expected to have significant advantage over the current supportive therapy. Basic knowledge obtained about the structure and function of BTK and the growth and development of B cell progenitors will be translated into a pre- clinical human cellular model for genetic therapy. This will include the isolation and manipulation of stem cells and B cell progenitors, and the construction of viral vectors to efficiently transfer the kinase gene into such cells. Such genetically altered cells will be assessed for viability, developmental potential and possible deleterious effects in the human-scid mouse chimera model. Information gained from these studies is viewed as critical to the development of direct clinical testing of this therapy in affected individuals
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