title: Amelioration of murine sickle cell disease by nonablative conditioning and γ-globin gene-corrected bone marrow cells.
abstract: Patients with severe sickle cell disease (SCD) are candidates for gene therapy using autologous hematopoietic stem cells (HSCs), but concomitant multi-organ disease may contraindicate pretransplant conditioning with full myeloablation. We tested whether nonmyeloablative conditioning, a regimen used successfully for allogeneic bone marrow transplantation of adult SCD patients, allows engraftment of γ-globin gene-corrected cells to a therapeutic level in the Berkeley mouse model of SCD. Animals transplanted according to this regimen averaged 35% engraftment of transduced hematopoietic stem cells with an average vector copy < 2.0. Fetal hemoglobin (HbF) levels ranged from 20 to 44% of total hemoglobin and approximately two-thirds of circulating red blood cells expressed HbF detected by immunofluorescence (F-cells). Gene therapy treatment of SCD mice ameliorated anemia, reduced hyperleukocytosis, improved renal function, and reduced iron accumulation in liver, spleen, and kidneys. Thus, modest levels of chimerism with donor cells expressing high levels of HbF from an insulated γ-globin lentiviral vector can improve the pathology of SCD in mice, thereby illustrating a potentially safe and effective strategy for gene therapy in humans.
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital , Memphis, TN, USA.
authors.forename: Tamara I
authors.initials: TI
authors.lastname: Pestina
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital , Memphis, TN, USA.
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Hargrove
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital , Memphis, TN, USA.
authors.forename: Huifen
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital , Memphis, TN, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Mead
authors.affiliation: Department of Epidemiology and Biostatistics, University of Memphis School of Public Health , Memphis, TN, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Smeltzer
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital , Memphis, TN, USA.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology and Simmons Cancer Institute, Southern Illinois University School of Medicine , Springfield, IL, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilber
authors.affiliation: Department of Hematology, St. Jude Children's Research Hospital , Memphis, TN, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Persons