1. ¹Division of Experimental Hematology, Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
2. ²Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
3. ³Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Correspondence: Derek A. Persons, Division of Experimental Hematology, Department of Hematology, 262 Danny Thomas Place, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. E-mail: derek.persons@stjude.org

Received 22 October 2008; Accepted 27 October 2008; Published online 2 December 2008.

Abstract

Increased levels of red cell fetal hemogloblin, whether due to hereditary persistence of expression or from induction with hydroxyurea therapy, effectively ameliorate sickle cell disease (SCD). Therefore, we developed erythroid-specific, -globin lentiviral vectors for hematopoietic stem cell (HSC)-targeted gene therapy with the goal of permanently increasing fetal hemoglobin (HbF) production in sickle red cells. We evaluated two different -globin lentiviral vectors for therapeutic efficacy in the BERK sickle cell mouse model. The first vector, V5, contained the -globin gene driven by 3.1 kb of -globin regulatory sequences and a 130-bp -globin promoter. The second vector, V5m3, was identical except that the -globin 3'-untranslated region (3'-UTR) was replaced with the -globin 3'-UTR. Adult erythroid cells have -globin mRNA 3'-UTR-binding proteins that enhance -globin mRNA stability and we postulated this design might enhance -globin expression. Stem cell gene transfer was efficient and nearly all red cells in transplanted mice expressed human -globin. Both vectors demonstrated efficacy in disease correction, with the V5m3 vector producing a higher level of -globin mRNA which was associated with high-level correction of anemia and secondary organ pathology. These data support the rationale for a gene therapy approach to SCD by permanently enhancing HbF using a -globin lentiviral vector.