@article{077a6d7479b6429f8b0f0019818572e8,
title = "Polycytidine tract deletion from microRNA-detargeted oncolytic Mengovirus optimizes the therapeutic index in a murine multiple myeloma model",
abstract = "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 (MC0) 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 (MC24-NC and MC37-NC) replicated in vitro 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 MC0-NC led to faster tumor responses than MC24-NC or MC37-NC, with combined durable complete response rates of 75%, 0.5%, and 30%, respectively. Secondary viremia was higher following MC0-NC versus MC24-NC or MC37-NC therapy. Sequence analysis of virus progeny from treated mice revealed a high prevalence of miRT sequences loss among MC24- and MC37- viral genomes, but not in MC0-NC. Overall, MC0-NC was capable of stably retaining miRT sites and provided a more effective treatment and is therefore our lead Mengovirus candidate for clinical translation.",
keywords = "Mengovirus, microRNA, microRNA detargeting, multiple myeloma, oncolytic virotherapy, oncolytic virus, picornavirus, polyC tract",
author = "Velia Penza and Maroun, {Justin W.} and Nace, {Rebecca A.} and Schulze, {Autumn J.} and Russell, {Stephen J.}",
note = "Funding Information: The authors thank Sara L. Anderson for the expert secretarial assistance. The authors also thank Ann C. Palmenberg of the University of Wisconsin for the kind gifts of the pF/R-wt and Rz-pMwt plasmids and communications regarding their use, and T.C. Wu of Johns Hopkins University, Department of Gynecologic Pathology for the kind gift of the TC-1 cell line. The authors respect and acknowledge the contribution of Henrietta Lacks and HeLa cells to biomedical research and of all other human tissue donors. V.P. was supported by the Mayo Clinic Graduate School of Biological Science. J.W.M. was supported by the Medical Scientist Training Program at the Mayo Clinic Alix School of Medicine. The present work was funded by the Mayo Clinic Foundation and the National Institutes of Health (NIH) (grants R01CA207386). The graphical abstract for this manuscript was created with Biorender.com. Conception and design: V.P. A.J.S. and S.J.R. Development of methodology: V.P. J.W.M. A.J.S. Acquisition of data from in vitro and in vivo experiments: V.P. R.A.N. Analysis and interpretation: V.P. J.W.M. and A.J.S. Writing, review, and revision of the manuscript: V.P. A.J.S. and S.J.R. Study supervision: A.J.S. and S.J.R. S.J.R. is chief executive officer at Vyriad, an oncolytic virus company. S.J.R. and Mayo Clinic hold equity in Vyriad. Funding Information: The authors thank Sara L. Anderson for the expert secretarial assistance. The authors also thank Ann C. Palmenberg of the University of Wisconsin for the kind gifts of the pF/R-wt and Rz-pMwt plasmids and communications regarding their use, and T.C. Wu of Johns Hopkins University, Department of Gynecologic Pathology for the kind gift of the TC-1 cell line. The authors respect and acknowledge the contribution of Henrietta Lacks and HeLa cells to biomedical research and of all other human tissue donors. V.P. was supported by the Mayo Clinic Graduate School of Biological Science. J.W.M. was supported by the Medical Scientist Training Program at the Mayo Clinic Alix School of Medicine . The present work was funded by the Mayo Clinic Foundation and the National Institutes of Health (NIH) (grants R01CA207386 ). The graphical abstract for this manuscript was created with Biorender.com . Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2023",
month = mar,
day = "16",
doi = "10.1016/j.omto.2022.11.006",
language = "English (US)",
volume = "28",
pages = "15--30",
journal = "Molecular Therapy - Oncolytics",
issn = "2372-7705",
publisher = "Nature Publishing Group",
}