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Title: Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies
Authors: Kanit Bhukhai
Edouard de Dreuzy
Marie Giorgi
Charlotte Colomb
Olivier Negre
Maria Denaro
Béatrix Gillet-Legrand
Joëlle Cheuzeville
Anaïs Paulard
Hélène Trebeden-Negre
Suparerk Borwornpinyo
Karine Sii-Felice
Leila Maouche
Julian D. Down
Phillippe Leboulch
Emmanuel Payen
Bluebird Bio, Inc.
Massachusetts Institute of Technology
Brigham and Women's Hospital
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Hôpital Universitaire Pitié Salpêtrière
Mahidol University
CEA Fontenay aux Roses
Keywords: Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 7-Feb-2018
Citation: Molecular Therapy. Vol.26, No.2 (2018), 480-495
Abstract: © 2017 The Authors Although gene transfer to hematopoietic stem cells (HSCs) has shown therapeutic efficacy in recent trials for several individuals with inherited disorders, transduction incompleteness of the HSC population remains a hurdle to yield a cure for all patients with reasonably low integrated vector numbers. In previous attempts at HSC selection, massive loss of transduced HSCs, contamination with non-transduced cells, or lack of applicability to large cell populations has rendered the procedures out of reach for human applications. Here, we fused codon-optimized puromycin N-acetyltransferase to herpes simplex virus thymidine kinase. When expressed from a ubiquitous promoter within a complex lentiviral vector comprising the βAT87Q-globin gene, viral titers and therapeutic gene expression were maintained at effective levels. Complete selection and preservation of transduced HSCs were achieved after brief exposure to puromycin in the presence of MDR1 blocking agents, suggesting the procedure's suitability for human clinical applications while affording the additional safety of conditional suicide. Recent clinical trials have demonstrated the benefits of hematopoietic gene therapy using lentiviral vectors. In this paper, Payen and colleagues describe a method to maximize the proportion of genetically modified human hematopoietic stem cells while limiting the mean vector copy number.
ISSN: 15250024
Appears in Collections:Scopus 2018

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