RRC ID 44947
Author Zimmermann M, Armeanu-Ebinger S, Bossow S, Lampe J, Smirnow I, Schenk A, Lange S, Weiss TS, Neubert W, Lauer UM, Bitzer M.
Title Attenuated and protease-profile modified sendai virus vectors as a new tool for virotherapy of solid tumors.
Journal PLoS ONE
Abstract Multiple types of oncolytic viruses are currently under investigation in clinical trials. To optimize therapeutic outcomes it is believed that the plethora of different tumor types will require a diversity of different virus types. Sendai virus (SeV), a murine parainfluenza virus, displays a broad host range, enters cells within minutes and already has been applied safely as a gene transfer vector in gene therapy patients. However, SeV spreading naturally is abrogated in human cells due to a lack of virus activating proteases. To enable oncolytic applications of SeV we here engineered a set of novel recombinant vectors by a two-step approach: (i) introduction of an ubiquitously recognized cleavage-motive into SeV fusion protein now enabling continuous spreading in human tissues, and (ii) profound attenuation of these rSeV by the knockout of viral immune modulating accessory proteins. When employing human hepatoma cell lines, newly generated SeV variants now reached high titers and induced a profound tumor cell lysis. In contrast, virus release from untransformed human fibroblasts or primary human hepatocytes was found to be reduced by about three log steps in a time course experiment which enables the cumulation of kinetic differences of the distinct phases of viral replication such as primary target cell infection, target cell replication, and progeny virus particle release. In a hepatoma xenograft animal model we found a tumor-specific spreading of our novel recombinant SeV vectors without evidence of biodistribution into non-malignant tissues. In conclusion, we successfully developed novel tumor-selective oncolytic rSeV vectors, constituting a new tool for virotherapy of solid tumors being ready for further preclinical and clinical development to address distinct tumor types.
Volume 9(3)
Pages e90508
Published 2014
DOI 10.1371/journal.pone.0090508
PII PONE-D-13-34078
PMID 24598703
PMC PMC3944018
MeSH Amino Acid Sequence Animals Base Sequence Cell Line, Tumor Cell Survival Cercopithecus aethiops Genetic Vectors Humans Mice, Inbred BALB C Mice, Nude Neoplasm Proteins / metabolism Neoplasm Transplantation Neoplasms / enzymology Neoplasms / therapy* Oncolytic Virotherapy* Oncolytic Viruses / genetics Oncolytic Viruses / physiology Peptide Hydrolases / metabolism Protein Engineering Proteolysis Sendai virus / genetics* Sendai virus / physiology Vero Cells Viral Load Viral Proteins / metabolism Virus Replication
IF 2.766
Times Cited 4
Human and Animal Cells