Correction of Sickle Cell Disease in Transgenic Mouse Models by Gene Therapy

作者：Robert Pawliuk, Karen A. Westerman, Mary E. Fabry, Emmanuel Payen, Robert Tighe, Eric E. Bouhassira, Seetharama A. Acharya, James Ellis, Irving M. London, Connie J. Eaves, R. Keith Humphries, Yves Beuzard, Ronald L. Nagel, Philippe Leboulch · 发表于：Science · 年份：2001 · DOI：10.1126/science.1065806 · 被引用次数：584 · 研究领域：Hemoglobinopathies and Related Disorders、Iron Metabolism and Disorders、Erythrocyte Function and Pathophysiology

Sickle cell disease (SCD) is caused by a single point mutation in the human betaA globin gene that results in the formation of an abnormal hemoglobin [HbS (alpha2betaS2)]. We designed a betaA globin gene variant that prevents HbS polymerization and introduced it into a lentiviral vector we optimized for transfer to hematopoietic stem cells and gene expression in the adult red blood cell lineage. Long-term expression (up to 10 months) was achieved, without preselection, in all transplanted mice with erythroid-specific accumulation of the antisickling protein in up to 52% of total hemoglobin and 99% of circulating red blood cells. In two mouse SCD models, Berkeley and SAD, inhibition of red blood cell dehydration and sickling was achieved with correction of hematological parameters, splenomegaly, and prevention of the characteristic urine concentration defect.