REGULATED HIGH-LEVEL HUMAN BETA-GLOBIN GENE-EXPRESSION IN ERYTHROID-CELLS FOLLOWING RECOMBINANT ADENO-ASSOCIATED VIRUS-MEDIATED GENE-TRANSFER

Gene therapy approaches for beta-thalassemia and sickle cell anemia fo cus on the transfer of a human beta-globin gene into the patient's hem atopoietic stem cells (HSC). Expression of the transferred sequences s hould be erythroid specific and match the expression of the endogenous alpha-globin genes in adult erythropoiesis. Here we explore the poten tial of recombinant adeno-associated virus (AAV) vectors for human bet a-globin gene transfer. We have constructed a recombinant AAV-vector c ontaining a human beta-globin gene together with DNasel hypersensitive sites 4, 3 and 2 of the human beta-globin locus control region. The v ector replicates to high titers and can efficiently transduce hematopo ietic and non-hematopoietic cells. In transduced and G418 selected mur ine erythroleukemia (MEL) cell clones, human beta-globin gene expressi on was regulated and reached levels comparable to endogenous murine be ta(maj). These data show that AAV-vectors are promising tools in gene therapy approaches for the haemoglobinopathies.