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 
A globin gene that results in the formation of
an abnormal hemoglobin [HbS
(
2S2)]. We designed
a 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
