MicroRNA-detargeting proves more effective than deletion of a virulence factor for improving safety of oncolytic Mengovirus in athymic nude mouse model

Published on Dec 17, 2021in Molecular Therapy - Oncolytics4.115
· DOI :10.1016/J.OMTO.2021.08.011
Suryawanshi Yr (Mayo Clinic), Rebecca Nace13
Estimated H-index: 13
(Mayo Clinic)
+ 1 AuthorsAutumn J. Schulze2
Estimated H-index: 2
(Mayo Clinic)
Sources
Abstract
Abstract null null A dual microRNA-detargeted oncolytic Mengovirus, vMC24NC, proved highly effective against a murine plasmacytoma in an immunocompetent syngeneic mouse model, however there remains the concern of escape mutant development and the potential for toxicity in severely immune compromised cancer patients when used as an oncolytic virus. Therefore, we sought to compare the safety and efficacy profiles of an attenuated Mengovirus containing a virulence gene deletion versus vMC24NC in an immune deficient xenograft mouse model of human glioblastoma. A Mengovirus construct vMC24ΔL, wherein the gene coding for the leader protein, a virulence factor, was deleted and used for comparison. The vMC24ΔL induced significant levels of toxicity following treatment of subcutaneous human glioblastoma (U87-MG) xenografts as well as when injected intracranially in athymic nude mice, reducing the overall survival. The in vivo toxicity of vMC24ΔL was associated with viral replication in nervous and cardiac tissue. In contrast, microRNA-detargeted vMC24NC demonstrated excellent efficacy against U87-MG subcutaneous xenografts and improved overall survival significantly as compared to that of control mice without toxicity. These results reinforce microRNA-detargeting as an effective strategy for ameliorating unwanted toxicities of oncolytic picornaviruses and substantiate vMC24NC as an ideal candidate for clinical development against certain cancers both in immuno-competent and -deficient hosts.
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