The best opportunity for a cure is hematopoietic stem cell (HSC) transplantation, but this treatment is only available to persons who have human leukocyte antigen-matched donors. 3-5 The result is a life-threatening anemia that requires regular red cell transfusion therapy for survival and quality of life. 2 Intramedullary apoptosis of developing erythroid cells is prominent, whereas those cells that do survive and mature to enucleated red cells have significant abnormalities and a greatly reduced life span in the periphery. 1 Intracellular precipitation of excess α-globin chains in bone marrow erythroid cells underlies the disease pathophysiology. One such disorder, β-thalassemia major, results from reduced (β +) or absent (β 0) expression of the β-globin chain of adult Hb (α 2β 2 HbA) because of a variety of deletions and mutations in the β-globin gene or its upstream regulatory elements. The hemoglobin (Hb) disorders are highly prevalent, autosomal recessive genetic diseases in which coinheritance of 2 defective globin alleles results in severe hematologic disease. These observations suggest that both lentiviral-mediated γ-globin gene addition and genetic reactivation of endogenous γ-globin genes have potential to provide therapeutic HbF levels to patients with β-globin deficiency. For β-thalassemic CD34 + cells, similar gene transfer efficiencies achieved HbF production ranging from 45% to 60%, resulting in up to a 3-fold increase in the total cellular Hb content. Erythroid progeny of normal CD34 + cells demonstrated levels of HbF up to 21% per vector copy. Lentiviral vectors encoding (1) a human γ-globin gene with or without an insulator, (2) a synthetic zinc-finger transcription factor designed to interact with the γ-globin gene promoters, or (3) a short-hairpin RNA targeting the γ-globin gene repressor, BCL11A, were tested. We used an in vitro model of human erythropoiesis to assay for enhanced production of HbF after gene delivery into CD34 + cells obtained from mobilized peripheral blood of normal adults or steady-state bone marrow from patients with β-thalassemia major. Increased levels of fetal hemoglobin (α 2γ 2 HbF), such as occurs with hereditary persistence of HbF, ameliorate the severity of β-thalassemia, raising the potential for genetic therapy directed at enhancing HbF. Β-Thalassemia major results from severely reduced or absent expression of the β-chain of adult hemoglobin (α 2β 2 HbA).
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