ENT department, Chelsea and Westminster NHS Foundation Trust, London, UK.
Department of Veterinary Clinical Sciences, University of Copenhagen, Copenhagen, Denmark.
Cancer Gene Ther. 2022 Nov;29(11):1628-1635. doi: 10.1038/s41417-022-00480-3. Epub 2022 May 20.
There is a great demand for improved oncolytic viruses that selectively replicate within cancer cells while sparing normal cells. Here, we describe a novel oncolytic adenovirus, Ixovex-1, that obtains a cancer-selective replication phenotype by modulating the level of expression of the different, alternatively spliced E1B mRNA isoforms. Ixovex-1 is a recombinant adenovirus that carries a single point mutation in the E1B-93R 3' splice acceptor site that results in overexpression of the E1B-156R splice isoform. In this paper, we studied the characteristics of this novel oncolytic adenovirus by validating its in vitro behaviour in a panel of normal cells and cancer cells. We additionally studied its anti-tumour efficacy in vivo. Ixovex-1 significantly inhibited tumour growth and prolonged survival of mice in an immune-deficient lung carcinoma tumour implantation model. In complementation experiments, overexpression of E1B-156R was shown to increase the oncolytic index of both Ad5wt and ONYX-015. In contrast to prior viruses of similar type, Ixovex-1 includes a functional E3B region for better in vivo efficacy. Throughout this study, the Ixovex-1 virus has been proven to be superior in competency compared to a virus with multiple deletions.
目前，人们对能够选择性在癌细胞内复制而不损伤正常细胞的改良溶瘤病毒有很大的需求。在这里，我们描述了一种新型溶瘤腺病毒，Ixovex-1，它通过调节不同的、可变剪接的 E1B mRNA 异构体的表达水平获得了癌症选择性复制表型。Ixovex-1 是一种重组腺病毒，在 E1B-93R 3' 剪接受体位点携带单点突变，导致 E1B-156R 剪接异构体的过表达。在本文中，我们通过在一系列正常细胞和癌细胞中验证其体外行为来研究这种新型溶瘤腺病毒的特性。我们还研究了其在体内的抗肿瘤功效。在免疫缺陷型肺癌肿瘤植入模型中，Ixovex-1 显著抑制肿瘤生长并延长小鼠的存活时间。在互补实验中，E1B-156R 的过表达增加了 Ad5wt 和 ONYX-015 的溶瘤指数。与类似类型的先前病毒不同，Ixovex-1 包含功能性 E3B 区域，以提高体内功效。在整个研究过程中，与具有多种缺失的病毒相比，Ixovex-1 病毒在效能方面表现出优越性。
