State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China.
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China; Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Mol Ther. 2020 Jun 3;28(6):1533-1546. doi: 10.1016/j.ymthe.2020.04.005. Epub 2020 Apr 14.
Malignant gliomas, the most lethal type of primary brain tumor, continue to be a major therapeutic challenge. Here, we found that enterovirus A71 (EV-A71) can be developed as a novel oncolytic agent against malignant gliomas. EV-A71 preferentially infected and killed malignant glioma cells relative to normal glial cells. The virus receptor human scavenger receptor class B, member 2 (SCARB2), and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)-mediated cell death were involved in EV-A71-induced oncolysis. In mice with implanted subcutaneous gliomas, intraneoplastic inoculation of EV-A71 caused significant tumor growth inhibition. Furthermore, in mice bearing intracranial orthotopic gliomas, intraneoplastic inoculation of EV-A71 substantially prolonged survival. By insertion of brain-specific microRNA-124 (miR124) response elements into the viral genome, we improved the tumor specificity of EV-A71 oncolytic therapy by reducing its neurotoxicity while maintaining its replication potential and oncolytic capacity in gliomas. Our study reveals that EV-A71 is a potent oncolytic agent against malignant gliomas and may have a role in treating this tumor in the clinical setting.
恶性神经胶质瘤是最致命的原发性脑肿瘤，一直是治疗的主要挑战。在这里，我们发现肠道病毒 A71（EV-A71）可以开发为针对恶性神经胶质瘤的新型溶瘤剂。EV-A71 优先感染和杀死恶性神经胶质瘤细胞，而相对正常神经胶质细胞。病毒受体人清道夫受体 B 成员 2（SCARB2）和佛波醇-12-肉豆蔻酸-13-醋酸酯诱导蛋白 1（PMAIP1）介导的细胞死亡参与了 EV-A71 诱导的溶瘤作用。在植入皮下神经胶质瘤的小鼠中，瘤内接种 EV-A71 可显著抑制肿瘤生长。此外，在颅内原位神经胶质瘤小鼠中，瘤内接种 EV-A71 可显著延长生存期。通过将脑特异性 microRNA-124（miR124）反应元件插入病毒基因组中，我们通过降低其神经毒性，同时保持其在神经胶质瘤中的复制潜力和溶瘤能力，提高了 EV-A71 溶瘤治疗的肿瘤特异性。我们的研究表明，EV-A71 是一种针对恶性神经胶质瘤的有效溶瘤剂，可能在临床治疗这种肿瘤中发挥作用。
