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Open Access Green as soon as Postprint is submitted to ZB.
miR-375- and miR-1-regulated coxsackievirus B3 has no pancreas and heart toxicity but strong antitumor efficiency in colorectal carcinomas.
Hum. Gene Ther. 32, 216-230 (2021)
Coxsackievirus B3 (CVB3) has strong oncolytic activity in colorectal carcinoma but it also infects the pancreas and the heart. To improve the safety of the virus, here we investigated whether pancreas and cardiac toxicity can be prevented by insertion of target sites (TS), which are complementary to miR-375 and miR-1 into the viral genome. Although miR-375 and miR-1 are abundantly expressed in the pancreas and in the heart, respectively, their expression levels are low in colorectal carcinomas, which allows the carcinomas to be selectively attacked. To investigate the importance of the microRNAs, two viruses were engineered, H3N-375TS containing only miR-375TS and H3N-375/1TS containing miR-375TS and miR-1TS. In vitro, both viruses replicated in and lysed colorectal carcinoma cells, similar to a nontargeted control virus H3N-39TS, whereas they were strongly attenuated in cell lines transiently or endogenously expressing the corresponding microRNAs. In vivo, the control virus H3N-39TS induced strong infection of the pancreas and the heart, which led to fatal disease within 4 days after a single intratumoral virus injection in mice xenografted with colorectal DLD-1 cell tumors. In contrast, three intratumoral injections of H3N-375TS or H3N-375/1TS failed to induce virus-induced sickness. In the animals, both viruses were completely ablated from the pancreas and H3N-375/1TS was also ablated from the heart, whereas the cardiac titers of H3N-375TS were strongly reduced. Long-term investigations of the DLD-1 tumor model confirmed lack of virus-induced adverse effects in H3N-375TS- and H3N-375/1TS-treated mice. There was no mortality, and the pancreas and the heart were free of pathological alterations. Regarding the therapeutic efficiency, the treated animals showed high and long-lasting H3N-375TS and H3N-375/1TS persistence in the tumor and significantly slower tumor growth. These data demonstrate that miR-375- and miR-1-mediated virus detargeting from the pancreas and heart is a highly effective strategy to prevent toxicity of oncolytic CVB3.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Colorectal Cancer ; Coxsackievirus B3 ; Microrna ; Oncolytic Virus; Oncolytic Virus; Microrna; Rna; Transcription; Myocarditis; Survival; Strain; Target; Tumor
ISSN (print) / ISBN
1043-0342
e-ISSN
1557-7422
Quellenangaben
Volume: 32,
Issue: 3-4,
Pages: 216-230
Publisher
Mary Ann Liebert
Publishing Place
140 Huguenot Street, 3rd Fl, New Rochelle, Ny 10801 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute for Pancreatic Beta Cell Research (IPI)
Grants
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
Faculty of Medicine of the TU Dresden, Dresden, Germany
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus
Wilhelm Sander-Stiftung
Faculty of Medicine of the TU Dresden, Dresden, Germany
Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus
Wilhelm Sander-Stiftung