Hemoglobinopathies and thalassemias arise from genetic mutations resulting in changes in the coding region giving rise to mutant hemoglobins such as sickle cell anemia, or changes in transcription, processing or translation of the globin RNA transcript. Fetal hemoglobin provides a protective effect in sickle cell anemia by inhibiting polymerization of the mutant hemoglobin within the red blood cell. A more mild form of sickle cell anemia with high levels of fetal hemoglobin have been associated with individuals from Saudi Arabia and we have begun a genetic analysis of globin related mutations from this region to characterize the genetic lesions associated with various ethnic groups. To address therapeutic approaches to these genetic diseases, we are using a multiribozyme approach to target the mutant globin transcript. These have been successfully introduced to K562 cells to suppress alpha-globin production. Strategies are now in progress to target a beta-S-globin transcript. An alternate approach under current investigation is the use of chimeric RNA/DNA oligonucleotides to mediate site- directed mutagenesis via DNA repair mechanisms. The chimeric oligonucleotide composed of DNA and RNA residues in a duplex conformation is designed to form a stable triple helix with the nucleotide targeted for exchange in the center of the complex. Using K562 cells engineered to express beta-S globin transcripts as a model system and conventional PCR, we have not been able to detect reproducible successful targeting with a resolution of 10% correction. Other approaches to affect erythropoiesis and globin gene expression include alteration of the balance of transcription factors such as GATA-1, GATA-2 and SCL/Tal-1 in erythroid cultures and screening of chemical agents. Induced expression of GATA-2, and to a lesser extent GATA-1, in erythroid cells can modify globin expression. At high levels GATA-2 inhibits cell proliferation and induces a megakaryocytic phenotype while GATA-1 stimulates cell proliferation. These results suggest that manipulation of transcription factors may provide an alternate strategy to therapeutically increase fetal hemoglobin expression.
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