狒狒包膜 LV 有效地转导了人成体、胎儿和祖细胞 T 细胞,并纠正了 SCID-X1 T 细胞缺陷。
Baboon envelope LVs efficiently transduced human adult, fetal, and progenitor T cells and corrected SCID-X1 T-cell deficiency.
机构信息
Centre International de Recherche en Infectiologie, Université Lyon, Université Claude Bernard Lyon 1, INSERM, U1111, Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 5308, Ecole Normale Supérieure de Lyon, Lyon, France.
Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, and.
出版信息
Blood Adv. 2019 Feb 12;3(3):461-475. doi: 10.1182/bloodadvances.2018027508.
T cells represent a valuable tool for treating cancers and infectious and inherited diseases; however, they are mainly short-lived in vivo. T-cell therapies would strongly benefit from gene transfer into long-lived persisting naive T cells or T-cell progenitors. Here we demonstrate that baboon envelope glycoprotein pseudotyped lentiviral vectors (BaEV-LVs) far outperformed other LV pseudotypes for transduction of naive adult and fetal interleukin-7-stimulated T cells. Remarkably, BaEV-LVs efficiently transduced thymocytes and T-cell progenitors generated by culture of CD34 cells on Delta-like ligand 4 (Dll4). Upon NOD/SCIDγC engraftment, high transduction levels (80%-90%) were maintained in all T-cell subpopulations. Moreover, T-cell lineage reconstitution was accelerated in NOD/SCIDγC recipients after T-cell progenitor injection compared with hematopoietic stem cell transplantation. Furthermore, γC-encoding BaEV-LVs very efficiently transduced Dll4-generated T-cell precursors from a patient with X-linked severe combined immunodeficiency (SCID-X1), which fully rescued T-cell development in vitro. These results indicate that BaEV-LVs are valuable tools for the genetic modification of naive T cells, which are important targets for gene therapy. Moreover, they allowed for the generation of gene-corrected T-cell progenitors that rescued SCID-X1 T-cell development in vitro. Ultimately, the coinjection of LV-corrected T-cell progenitors and hematopoietic stem cells might accelerate T-cell reconstitution in immunodeficient patients.
T 细胞是治疗癌症、感染性和遗传性疾病的一种有价值的工具;然而,它们在体内主要是短暂存在的。T 细胞疗法将从基因转移到长寿命的持续存在的幼稚 T 细胞或 T 细胞祖细胞中获益匪浅。在这里,我们证明了狨猴包膜糖蛋白假型慢病毒载体(BaEV-LVs)在转导幼稚成人和胎肝白细胞介素-7 刺激的 T 细胞方面远远优于其他 LV 假型。值得注意的是,BaEV-LVs 有效地转导了胸腺细胞和由 CD34 细胞在 Delta-like 配体 4(Dll4)上培养产生的 T 细胞祖细胞。在 NOD/SCIDγC 移植后,所有 T 细胞亚群中均保持了高转导水平(80%-90%)。此外,与造血干细胞移植相比,T 细胞祖细胞注射后,NOD/SCIDγC 受体中的 T 细胞谱系重建得到加速。此外,编码γC 的 BaEV-LVs 非常有效地转导了来自 X 连锁严重联合免疫缺陷(SCID-X1)患者的 Dll4 产生的 T 细胞前体,在体外完全挽救了 T 细胞发育。这些结果表明,BaEV-LVs 是用于幼稚 T 细胞基因修饰的有价值的工具,幼稚 T 细胞是基因治疗的重要靶标。此外,它们允许生成可纠正基因的 T 细胞祖细胞,该细胞可在体外挽救 SCID-X1 的 T 细胞发育。最终,LV 校正的 T 细胞祖细胞和造血干细胞的共同注射可能会加速免疫缺陷患者的 T 细胞重建。