In various embodiments a recombinant lentiviral vector is provided comprising an expression cassette comprising a nucleic acid construct comprising an anti-sickling human beta globin gene encoding an anti-sickling-beta globin polypeptide comprising the mutations Gly16Asp, Glu22Ala and Thr87Gln, where the lentiviral vector is a TAT-independent and self-inactivating (SIN). In certain embodiments the vector additionally contains one or more insulator elements. The vectors are useful in gene therapy for the treatment of sickle cell disease.
