title: Correction of sickle cell disease in transgenic mouse models by gene therapy.
abstract: 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.
authors.affiliation: Harvard-MIT, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pawliuk
authors.forename: K A
authors.initials: KA
authors.lastname: Westerman
authors.forename: M E
authors.initials: ME
authors.lastname: Fabry
authors.forename: E
authors.initials: E
authors.lastname: Payen
authors.forename: R
authors.initials: R
authors.lastname: Tighe
authors.forename: E E
authors.initials: EE
authors.lastname: Bouhassira
authors.forename: S A
authors.initials: SA
authors.lastname: Acharya
authors.forename: J
authors.initials: J
authors.lastname: Ellis
authors.forename: I M
authors.initials: IM
authors.lastname: London
authors.forename: C J
authors.initials: CJ
authors.lastname: Eaves
authors.forename: R K
authors.initials: RK
authors.lastname: Humphries
authors.forename: Y
authors.initials: Y
authors.lastname: Beuzard
authors.forename: R L
authors.initials: RL
authors.lastname: Nagel
authors.forename: P
authors.initials: P
authors.lastname: Leboulch
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics / Q000628:therapy*; D000818:Animals; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006451:Hemoglobin, Sickle / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D019901:Locus Control Region; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010108:Oxyhemoglobins / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013789:Thalassemia / Q000235:genetics / Q000628:therapy; D014161:Transduction, Genetic; D019076:Transgenes; D055544:beta-Globins
chemical_list: D006451:Hemoglobin, Sickle; D010108:Oxyhemoglobins; D012333:RNA, Messenger; C443665:beta(A-T87Q) globin; D055544:beta-Globins; D005914:Globins