Publication: Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies
Issued Date
2018-02-07
Resource Type
ISSN
15250024
15250016
15250016
Other identifier(s)
2-s2.0-85041531747
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Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular Therapy. Vol.26, No.2 (2018), 480-495
Suggested Citation
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 Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies. Molecular Therapy. Vol.26, No.2 (2018), 480-495. doi:10.1016/j.ymthe.2017.10.015 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/45246
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Title
Ex Vivo Selection of Transduced Hematopoietic Stem Cells for Gene Therapy of β-Hemoglobinopathies
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.