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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.
AuthorsFarid Boulad, Xiuyan Wang, Jinrong Qu, Clare Taylor, Leda Ferro, Garyfalia Karponi, Shirley Bartido, Patricia Giardina, Glenn Heller, Susan E Prockop, Aurelio Maggio, Michel Sadelain, Isabelle Rivière
JournalBlood (Blood) Vol. 123 Issue 10 Pg. 1483-6 (Mar 6 2014) ISSN: 1528-0020 [Electronic] United States
PMID24429337 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD34
  • beta-Globins
Topics
  • Animals
  • Antigens, CD34 (metabolism)
  • Colony-Forming Units Assay
  • Disease Models, Animal
  • Erythroid Precursor Cells (metabolism)
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors (genetics)
  • Hematopoietic Stem Cell Mobilization
  • Hematopoietic Stem Cell Transplantation
  • Heterografts
  • Humans
  • Mice
  • Transduction, Genetic
  • beta-Globins (biosynthesis, genetics)
  • beta-Thalassemia (genetics, metabolism, therapy)

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