Coordinated beta-globin expression and alpha2-globin reduction in a multiplex lentiviral gene therapy vector for beta-thalassemia.

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Nualkaew T, Sii-Felice K, Giorgi M, McColl B, Gouzil J, Glaser A, Voon HPJ, Tee HY, Grigoriadis G, Svasti S, Fucharoen S, Hongeng S, Leboulch P, Payen E, Vadolas J

Coordinated beta-globin expression and alpha2-globin reduction in a multiplex lentiviral gene therapy vector for beta-thalassemia.

Mol Ther. 2021 Sep 1;29(9):2841-2853. doi: 10.1016/j.ymthe.2021.04.037. Epub 2021 May 1.

PubMed ID
33940155 [ View in PubMed
]
Abstract

A primary challenge in lentiviral gene therapy of beta-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, LVbeta-shalpha2, that allows coordinated expression of the therapeutic beta(A-T87Q)-globin gene and of an intron-embedded miR-30-based short hairpin RNA (shRNA) selectively targeting the alpha2-globin mRNA. Our approach was guided by the knowledge that moderate reduction of alpha-globin chain synthesis ameliorates disease severity in beta-thalassemia. We demonstrate that LVbeta-shalpha2 reduces alpha2-globin mRNA expression in erythroid cells while keeping alpha1-globin mRNA levels unchanged and beta(A-T87Q)-globin gene expression identical to the parent vector. Compared with the first beta(A-T87Q)-globin lentiviral vector that has received conditional marketing authorization, BB305, LVbeta-shalpha2 shows 1.7-fold greater potency to improve alpha/beta ratios. It may thus result in greater therapeutic efficacy and reliability for the most severe types of beta-thalassemia and provide an improved benefit/risk ratio regardless of the beta-thalassemia genotype.

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