Vázquez-Arreguín Karina, Gonzalez Alex, Webb Amy, Mo Xiaokui, Otani Yoshihiro, Kaur Balveen
Department of Pathology, Georgia Cancer Center at Augusta University, Augusta, GA 30912, USA.
Department of Neurosurgery, UTHealth Houston, Houston, TX 77030, USA.
Mol Ther Oncol. 2025 Feb 26;33(2):200961. doi: 10.1016/j.omton.2025.200961. eCollection 2025 Jun 18.
Oncolytic herpes simplex virus (HSV)-1-derived viruses are being developed for cancer treatment. Here, we describe the isolation of a novel strain of HSV-1 and its engineering to safely harness it as an oncolytic therapeutic. This strain (UT1a) was isolated from a de-identified consented patient biorepository. CRISPR-Cas9-based recombination was utilized to insert bacterial artificial chromosome (BAC) genes into the viral and locus, resulting in the deletion of both large and small subunits of the viral ribonucleotide reductase (RR). Subsequent deletion of viral genes encoding the neurovirulence factor γ34.5 resulted in OncoDelta (OncoD), a virus deleted for , , and both copies of . OncoD retained tumor-cell-specific cytotoxicity and replication; was safe and non-toxic in intracranial injections in naive mice up to doses of 5 × 10, the maximal injectable dose for OncoD; and showed significant anti-tumor immune-activating potential in multiple tumor models. Transcriptome profiling of OncoD showed that it impaired DNA damage repair pathways and hence synergized with radiation to improve therapeutic response and .
溶瘤单纯疱疹病毒1型（HSV-1）衍生病毒正被开发用于癌症治疗。在此，我们描述了一种新型HSV-1毒株的分离及其工程改造，以便安全地将其用作溶瘤治疗剂。该毒株（UT1a）是从一个经过身份识别同意的患者生物样本库中分离出来的。利用基于CRISPR-Cas9的重组技术，将细菌人工染色体（BAC）基因插入病毒的 和 位点，导致病毒核糖核苷酸还原酶（RR）的大亚基和小亚基均被删除。随后删除编码神经毒力因子γ34.5的病毒 基因，产生了OncoDelta（OncoD），一种缺失了 、 和两个拷贝 的病毒。OncoD保留了肿瘤细胞特异性细胞毒性和复制能力；在未接触过该病毒的小鼠颅内注射中，高达5×10（OncoD的最大可注射剂量）的剂量下是安全无毒的；并且在多个肿瘤模型中显示出显著的抗肿瘤免疫激活潜力。OncoD的转录组分析表明，它损害了DNA损伤修复途径，因此与辐射协同作用以改善治疗反应 和 。
