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Science 14 December 2001:
Vol. 294. no. 5550, pp. 2368 - 2371
DOI: 10.1126/science.1065806
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Reports

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

Robert Pawliuk,12 Karen A. Westerman,12 Mary E. Fabry,3 Emmanuel Payen,4 Robert Tighe,12 Eric E. Bouhassira,3 Seetharama A. Acharya,3 James Ellis,5 Irving M. London,16 Connie J. Eaves,7 R. Keith Humphries,7 Yves Beuzard,4 Ronald L. Nagel,3 Philippe Leboulch1248*

Sickle cell disease (SCD) is caused by a single point mutation in the human beta A globin gene that results in the formation of an abnormal hemoglobin [HbS (alpha 2beta S2)]. We designed a beta A 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.

1 Harvard-MIT, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2 Genetix Pharmaceuticals, Cambridge, MA 02139, USA.
3 Division of Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
4 INSERM EMI 0111, Hôpital Saint-Louis, 75010 Paris, France.
5 Department of Genetics, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
6 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7 The Terry Fox Laboratory and the University of British Columbia, Vancouver, BC V5Z3L6, Canada.
8 Harvard Medical School and Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115 USA.
*   To whom correspondence should be addressed. E-mail: pleboulch{at}mit.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)