Over 10% of patients with a fatal neurodegenerative disease who received bluebird bio’s FDA-approved gene therapy Skysona (elivaldogene autotemcel) have developed hematological cancers, further highlighting the well-known risks of using lentiviral vectors. The patients were treated with Skysona to slow the progression of cerebral adrenoleukodystrophy (CALD), an X-linked rare inherited neurodegenerative disease that affects a peroxisomal fatty acid transporter central to fatty acid metabolism. The mutation leads a toxic build-up of fatty acids, particularly in the white matter in brain and spinal cord and the adrenal glands. Skysona comprises autologous CD34⁺ cells engineered ex vivo to express the ABCD1 gene, which encodes a protein implicated in adrenoleukodystrophy.

Six of 67 patients had developed myelodysplastic syndrome and a seventh developed acute myeloid leukemia, between 14 and 92 months after treatment. Skysona uses a replication-deficient, HIV-1-derived vector named Lenti-D that contains the synthetic promoter MNDU3, which drives strong gene expression in multiple cell types. Six of the cases were associated with the expansion of a cell clone containing at least one vector insertion in a known proto-oncogene — five in MECOM and one in its closely related homologue PRDM16, the study authors report. The problems may not have been solely due to the lentiviral vector, however. Because six of the seven cases occurred in the ALD-104 study, the myeloablative conditioning regimen may also have been a contributory factor — in ALD-104, participants received busulfan and fludarabine, whereas in ALD-102 busulfan and cyclophosphamide were used. The patients who developed cancer were treated successfully, except for one who died after developing graft-versus-host disease and a lung infection. Given the life-threatening nature of CALD, the study can be considered a clinical success, but the possibility of further cancer cases cannot be eliminated.

在接受 bluebird bio FDA 批准的基因疗法 Skysona （elivaldogene autotemcel） 的致命性神经退行性疾病患者中，超过 10% 的患者患上了血液癌，这进一步凸显了使用慢病毒载体的众所周知的风险。患者接受 Skysona 治疗以减缓脑肾上腺脑白质营养不良 （CALD） 的进展，这是一种 X 连锁罕见的遗传性神经退行性疾病，影响脂肪酸代谢核心的过氧化物酶体脂肪酸转运蛋白。这种突变导致脂肪酸的毒性积累，尤其是在大脑和脊髓以及肾上腺的白质中。Skysona 由离体工程改造以表达 ABCD1 基因的自体 CD34 ⁺ 细胞组成，该基因编码一种与肾上腺脑白质营养不良有关的蛋白质。

67 名患者中有 6 名在治疗后 14 至 92 个月内发展为骨髓增生异常综合征，第 7 名发展为急性髓性白血病。Skysona 使用一种名为 Lenti-D 的复制缺陷型 HIV-1 衍生载体，该载体包含合成启动子 MNDU3，可在多种细胞类型中驱动强基因表达。研究作者报告说，其中 6 例与在已知原癌基因中包含至少一个载体插入的细胞克隆的扩增有关——5 例在 MECOM 中，1 例在其密切相关的同源物 PRDM16 中。然而，这些问题可能不仅仅是由于慢病毒载体造成的。由于 7 例病例中有 6 例发生在 ALD-104 研究中，清髓性预处理方案也可能是一个促成因素——在 ALD-104 中，参与者接受白消安和氟达拉滨，而在 ALD-102 中，使用白消安和环磷酰胺。患癌症的患者都得到了成功治疗，除了一名在发生移植物抗宿主病和肺部感染后死亡的患者。鉴于 CALD 危及生命的性质，该研究可以被认为是临床上的成功，但不能排除更多癌症病例的可能性。