Publication: Coordinated β-globin expression and α2-globin reduction in a multiplex lentiviral gene therapy vector for β-thalassemia
2
Issued Date
2021-09-01
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ISSN
15250024
15250016
15250016
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2-s2.0-85106639263
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Mahidol University
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SCOPUS
Bibliographic Citation
Molecular Therapy. Vol.29, No.9 (2021), 2841-2853
Suggested Citation
Tiwaporn Nualkaew, Karine Sii-Felice, Marie Giorgi, Bradley McColl, Julie Gouzil, Astrid Glaser, Hsiao P.J. Voon, Hsin Y. Tee, George Grigoriadis, Saovaros Svasti, Suthat Fucharoen, Suradej Hongeng, Philippe Leboulch, Emmanuel Payen, Jim Vadolas Coordinated β-globin expression and α2-globin reduction in a multiplex lentiviral gene therapy vector for β-thalassemia. Molecular Therapy. Vol.29, No.9 (2021), 2841-2853. doi:10.1016/j.ymthe.2021.04.037 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/76066
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Title
Coordinated β-globin expression and α2-globin reduction in a multiplex lentiviral gene therapy vector for β-thalassemia
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Abstract
A primary challenge in lentiviral gene therapy of β-hemoglobinopathies is to maintain low vector copy numbers to avoid genotoxicity while being reliably therapeutic for all genotypes. We designed a high-titer lentiviral vector, LVβ-shα2, that allows coordinated expression of the therapeutic βA-T87Q-globin gene and of an intron-embedded miR-30-based short hairpin RNA (shRNA) selectively targeting the α2-globin mRNA. Our approach was guided by the knowledge that moderate reduction of α-globin chain synthesis ameliorates disease severity in β-thalassemia. We demonstrate that LVβ-shα2 reduces α2-globin mRNA expression in erythroid cells while keeping α1-globin mRNA levels unchanged and βA-T87Q-globin gene expression identical to the parent vector. Compared with the first βA-T87Q-globin lentiviral vector that has received conditional marketing authorization, BB305, LVβ-shα2 shows 1.7-fold greater potency to improve α/β ratios. It may thus result in greater therapeutic efficacy and reliability for the most severe types of β-thalassemia and provide an improved benefit/risk ratio regardless of the β-thalassemia genotype.