RRC ID 77302
Author 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.
Title Coordinated β-globin expression and α2-globin reduction in a multiplex lentiviral gene therapy vector for β-thalassemia.
Journal Mol Ther
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.
Volume 29(9)
Pages 2841-2853
Published 2021-9-1
DOI 10.1016/j.ymthe.2021.04.037
PII S1525-0016(21)00251-3
PMID 33940155
PMC PMC8417505
MeSH Cell Line Cells, Cultured Down-Regulation Erythroid Cells / cytology Erythroid Cells / metabolism Genetic Vectors / administration & dosage* Genotype Humans K562 Cells Lentivirus / genetics Lentivirus / physiology MicroRNAs / antagonists & inhibitors Primary Cell Culture RNA, Small Interfering / genetics* Viral Load alpha-Globins / genetics* beta-Globins / genetics* beta-Thalassemia / genetics* beta-Thalassemia / therapy
IF 8.986
Human and Animal Cells HUDEP-2(RCB4557)