[HTML][HTML] Correction of murine sickle cell disease using γ-globin lentiviral vectors to mediate high-level expression of fetal hemoglobin

TI Pestina, PW Hargrove, D Jay, JT Gray, KM Boyd… - Molecular Therapy, 2009 - cell.com
TI Pestina, PW Hargrove, D Jay, JT Gray, KM Boyd, DA Persons
Molecular Therapy, 2009cell.com
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, γ-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
γ-globin lentiviral vectors for therapeutic efficacy in the BERK sickle cell mouse model. The …
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, γ-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 γ-globin lentiviral vectors for therapeutic efficacy in the BERK sickle cell mouse model. The first vector, V5, contained the γ-globin gene driven by 3.1 kb of β-globin regulatory sequences and a 130-bp β-globin promoter. The second vector, V5m3, was identical except that the γ-globin 3′-untranslated region (3′-UTR) was replaced with the β-globin 3′-UTR. Adult erythroid cells have β-globin mRNA 3′-UTR-binding proteins that enhance β-globin mRNA stability and we postulated this design might enhance γ-globin expression. Stem cell gene transfer was efficient and nearly all red cells in transplanted mice expressed human γ-globin. Both vectors demonstrated efficacy in disease correction, with the V5m3 vector producing a higher level of γ-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 γ-globin lentiviral vector.
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