Penza Velia, Maroun Justin W, Nace Rebecca A, Schulze Autumn J, Russell Stephen J
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55902, USA.
Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA.
Mol Ther Oncolytics. 2022 Dec 2;28:15-30. doi: 10.1016/j.omto.2022.11.006. eCollection 2023 Mar 16.
Mengovirus is an oncolytic picornavirus whose broad host range allows for testing in immunocompetent cancer models. Two pathogenicity-ablating approaches, polycytidine (polyC) tract truncation and microRNA (miRNA) targets insertion, eliminated the risk of encephalomyocarditis. To investigate whether a polyC truncated, miRNA-detargeted oncolytic Mengovirus might be boosted, we partially or fully rebuilt the polyC tract into the 5' noncoding region (NCR) of polyC-deleted (MC) oncolytic constructs (NC) carrying miRNA target (miRT) insertions to eliminate cardiac/muscular (miR-133b and miR-208a) and neuronal (miR-124) tropisms. PolyC-reconstituted viruses (MC-NC and MC-NC) replicated and showed the expected tropism restrictions, but reduced cytotoxicity and miRT deletions were frequently observed. In the MPC-11 immune competent mouse plasmacytoma model, both intratumoral and systemic administration of MC-NC led to faster tumor responses than MC-NC or MC-NC, with combined durable complete response rates of 75%, 0.5%, and 30%, respectively. Secondary viremia was higher following MC-NC versus MC-NC or MC-NC therapy. Sequence analysis of virus progeny from treated mice revealed a high prevalence of miRT sequences loss among MC- and MC- viral genomes, but not in MC-NC. Overall, MC-NC was capable of stably retaining miRT sites and provided a more effective treatment and is therefore our lead Mengovirus candidate for clinical translation.
脑心肌炎病毒是一种溶瘤微小核糖核酸病毒，其广泛的宿主范围使其可在免疫健全的癌症模型中进行测试。两种消除致病性的方法，即多聚胞苷（polyC）序列截断和微小核糖核酸（miRNA）靶点插入，消除了脑心肌炎的风险。为了研究截断polyC且去除miRNA靶点的溶瘤脑心肌炎病毒是否能得到增强，我们将polyC序列部分或完全重建到携带miRNA靶点（miRT）插入片段的polyC缺失（MC）溶瘤构建体（NC）的5'非编码区（NCR），以消除心脏/肌肉（miR-133b和miR-208a）和神经元（miR-124）嗜性。重建polyC的病毒（MC-NC和MC-NC）能够复制，并表现出预期的嗜性限制，但经常观察到细胞毒性降低和miRT缺失。在MPC-11免疫健全小鼠浆细胞瘤模型中，瘤内和全身给予MC-NC均比MC-NC或MC-NC导致更快的肿瘤反应，联合持久完全缓解率分别为75%、0.5%和30%。与MC-NC或MC-NC治疗相比，MC-NC治疗后的二次病毒血症更高。对治疗小鼠的病毒子代进行序列分析发现，MC-和MC-病毒基因组中miRT序列丢失的发生率很高，但MC-NC中没有。总体而言，MC-NC能够稳定保留miRT位点，并提供更有效的治疗，因此是我们用于临床转化的主要脑心肌炎病毒候选物。
