Journal
BLOOD
Volume 123, Issue 10, Pages 1483-1486Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-06-507178
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Funding
- National Institutes of Health, National Heart, Lung, and Blood Institute [P01 HL053750]
- National Cancer Institute [P30 CA08748]
- Stavros Niarchos Foundation
- Cooley's Anemia Foundation
- Cooley's Anemia International
- Leonardo Giambrone Foundation
- Piera Coutino Foundation
- Errant Gene Therapeutics, LLC
- Department of Pediatrics at Memorial Sloan-Kettering Cancer Center
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We conducted a pilot trial to investigate the safety and effectiveness of mobilizing CD34(+) hematopoietic progenitor cells (HPCs) in adults with beta-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 x 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 beta-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 beta-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.
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