Improved Globin Expression Vectors for Gene Therapy of Human Hemoglobinopathies

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PROJECT SUMMARY A lentiviral vector (CCLc- βAS3-FB {βAS3LV}) is being investigated for the treatment of severe sickle cell disease, however, it suffers from low titer, sub-optimal gene transfer to CD34+ hematopoietic stem cells (HSCs), and expression likely insufficient to definitively cure β-thalassemia (although sufficient to prevent sickling in pre-clinical studies). We hypothesize that there are known and unknown human β-globin genomic sequences within βAS3LV that are inhibiting vector performance. Studies outlined in this proposal will investigate how removal and/or addition of known or unknown elements within βAS3LV's human β-globin genomic sequences affect titer, gene delivery to HSCs, and expression of the anti-sickling βAS3-globin gene. The outcome of these studies will provide insight into how specific regulatory elements influence the performance of βAS3LV across multiple categories. Moreover, this research will yield a second generation of improved lentiviral vectors for efficiently transferring and effectively expressing the anti-sickling βAS3-globin gene for gene therapy of sickle cell disease.