title: Safe mobilization of CD34+ cells in adults with β-thalassemia and validation of effective globin gene transfer for clinical investigation.
abstract: We conducted a pilot trial to investigate the safety and effectiveness of mobilizing CD34(+) hematopoietic progenitor cells (HPCs) in adults with β-thalassemia major. We further assessed whether thalassemia patient CD34(+) HPCs could be transduced with a globin lentiviral vector under clinical conditions at levels sufficient for therapeutic implementation. All patients tolerated granulocyte colony-stimulating factor well with minimal side effects. All cell collections exceeded 8 × 10(6) CD34(+) cells/kg. Using clinical grade TNS9.3.55 vector, we demonstrated globin gene transfer averaging 0.53 in 3 validation runs performed under current good manufacturing practice conditions. Normalized to vector copy, the vector-encoded β-chain was expressed at a level approximating normal hemizygous protein output. Importantly, stable vector copy number (0.2-0.6) and undiminished vector expression were obtained in NSG mice 6 months posttransplant. Thus, we validated a safe and effective procedure for β-globin gene transfer in thalassemia patient CD34(+) HPCs, which we will implement in the first US trial in patients with severe inherited globin disorders. This trial is registered at www.clinicaltrials.gov as #NCT01639690.
authors.affiliation: Center for Cell Engineering.
authors.forename: Farid
authors.initials: F
authors.lastname: Boulad
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Wang
authors.forename: Jinrong
authors.initials: J
authors.lastname: Qu
authors.forename: Clare
authors.initials: C
authors.lastname: Taylor
authors.forename: Leda
authors.initials: L
authors.lastname: Ferro
authors.forename: Garyfalia
authors.initials: G
authors.lastname: Karponi
authors.forename: Shirley
authors.initials: S
authors.lastname: Bartido
authors.forename: Patricia
authors.initials: P
authors.lastname: Giardina
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Susan E
authors.initials: SE
authors.lastname: Prockop
authors.forename: Aurelio
authors.initials: A
authors.lastname: Maggio
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rivière
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D015672:Erythroid Precursor Cells / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D064593:Heterografts; D006801:Humans; D051379:Mice; D014161:Transduction, Genetic; D055544:beta-Globins / Q000096:biosynthesis / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*
chemical_list: D018952:Antigens, CD34; D055544:beta-Globins