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

Author:

Pawliuk Robert12,Westerman Karen A.12,Fabry Mary E.3,Payen Emmanuel4,Tighe Robert12,Bouhassira Eric E.3,Acharya Seetharama A.3,Ellis James5,London Irving M.16,Eaves Connie J.7,Humphries R. Keith7,Beuzard Yves4,Nagel Ronald L.3,Leboulch Philippe1248

Affiliation:

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.

Abstract

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

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference35 articles.

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2. H. F. Bunn in The Molecular Basis of Blood Diseases G. Stamatoyannopoulos A. Nienhuis P. W. Majerus H. Varmus Eds. (Saunders Philadelphia ed. 2 1994) pp. 207–256.

3. R. L. Nagel M. H. Steinberg in Disorders of Hemoglobin: Genetics Pathophysiology and Clinical Management M. H. Steinberg B. G. Forget D. R. Higgs R. L. Nagel Eds. (Cambridge Univ. Press Cambridge 2001) pp. 711–756.

4. Ligand-induced conformational dependence of hemoglobin in sickling interactions

5. Recombinant human hemoglobins designed for gene therapy of sickle cell disease.

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