title: Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia.
abstract: Recently, an engineered Homeobox-nucleoporin fusion gene, NUP98-HOXA10HD or NA10HD, was reported to expand and maintain murine hematopoietic stem cells (HSCs). We postulated that NA10HD would increase the number of human γ-globin-expressing cells to therapeutic levels. We developed a double gene lentiviral vector encoding both human γ-globin and NA10HD, which was used to transduce human peripheral blood CD34+cells and increased engraftment 2- to 2.5-fold at 15 weeks post-transplantation in immunodeficient mice. In β-thalassemic mice transplanted with β-thalassemic HSCs transduced with the γ-globin/NA10HD vector, the number of fetal hemoglobin (HbF)-expressing cells was significantly increased after 3 months, leading to resolution of the anemia. Furthermore, the increases in HbF were maintained at 6 months and persisted after secondary transplantation. In addition, NA10HD enrichment of transduced HSCs led to HbF increases without affecting homeostasis of the white blood cell lineages. Our results suggest that NA10HD increases the number of γ-globin-transduced HSCs that engraft, leading to an elevated number of fetal hemoglobin-containing red cells. These effects of NA10HD provide an improved platform for testing of the therapeutic efficacy of novel globin vectors and provide further impetus to develop safe and effective methods for selective expansion of genetically modified cells.
authors.affiliation: Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Hui Fen
authors.initials: HF
authors.lastname: Zhao
authors.affiliation: Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Allistair
authors.initials: A
authors.lastname: Abraham
authors.affiliation: Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Yoon-Sang
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Wang
authors.affiliation: Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Pestina
authors.affiliation: Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhan
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Keith
authors.initials: K
authors.lastname: Humphries
authors.affiliation: Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: arthur.nienhuis@stjude.org.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Nienhuis
authors.affiliation: Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Persons
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000378:metabolism; D023061:Gene Order; D018014:Gene Transfer Techniques; D056426:Genetic Loci; D005822:Genetic Vectors / Q000235:genetics*; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D017086:beta-Thalassemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D055545:gamma-Globins / Q000235:genetics*
chemical_list: D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D055545:gamma-Globins; C093350:nuclear pore complex protein 98; C069634:HOXA10 protein, human; D005319:Fetal Hemoglobin
keywords: NUP98HOXA10-HD fusion protein; gene therapy; resolution of the anemia; transduction; transplantation; β-thalassemic mice; γ-globin