MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy
Mengovirus, a member of the Picornaviridae family, has a broad cell tropism and can cause encephalitis and myocarditis in multiple mammalian species. Attenuation has been achieved by shortening the polycytidine tract in the 5′ noncoding region (NCR). A poly(C)-truncated strain of mengovirus, vMC24,...
| Main Authors: | , , , |
|---|---|
| Format: | Online |
| Language: | English |
| Published: |
American Society for Microbiology
2016
|
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810567/ |
| id |
pubmed-4810567 |
|---|---|
| recordtype |
oai_dc |
| spelling |
pubmed-48105672016-04-04 MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy Ruiz, Autumn J. Hadac, Elizabeth M. Nace, Rebecca A. Russell, Stephen J. Genome Replication and Regulation of Viral Gene Expression Mengovirus, a member of the Picornaviridae family, has a broad cell tropism and can cause encephalitis and myocarditis in multiple mammalian species. Attenuation has been achieved by shortening the polycytidine tract in the 5′ noncoding region (NCR). A poly(C)-truncated strain of mengovirus, vMC24, resulted in significant tumor regression in immunocompetent BALB/c mice bearing syngeneic MPC-11 plasmacytomas, but the associated toxicities were unacceptable. To enhance its safety profile, microRNA target sequences complementary to miR-124 or miR-125 (enriched in nervous tissue), miR-133 and miR-208 (enriched in cardiac tissue), or miR-142 (control; enriched in hematopoietic tissues) were inserted into the vMC24 NCRs. The microRNA-detargeted viruses showed reduced replication and cell killing specifically in cells expressing the cognate microRNAs, but certain insertions additionally were associated with nonspecific suppression of viral fitness in vivo. In vivo toxicity testing confirmed that miR-124 targets within the 5′ NCR suppressed virus replication in the central nervous system while miR-133 and miR-208 targets in the 3′ NCR suppressed viral replication in cardiac tissue. A dual-detargeted virus named vMC24-NC, with miR-124 targets in the 5′ NCR and miR-133 plus miR-208 targets in the 3′ NCR, showed the suppression of replication in both nervous and cardiac tissues but retained full oncolytic potency when administered by intratumoral (106 50% tissue culture infectious doses [TCID50]) or intravenous (107 to 108 TCID50) injection into BALB/c mice bearing MPC-11 plasmacytomas. Overall survival of vMC24-NC-treated tumor-bearing mice was significantly improved compared to that of nontreated mice. MicroRNA-detargeted mengoviruses offer a promising oncolytic virotherapy platform that merits further development for clinical translation. American Society for Microbiology 2016-03-28 /pmc/articles/PMC4810567/ /pubmed/26865716 http://dx.doi.org/10.1128/JVI.02810-15 Text en Copyright © 2016 Ruiz et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) . |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Ruiz, Autumn J. Hadac, Elizabeth M. Nace, Rebecca A. Russell, Stephen J. |
| spellingShingle |
Ruiz, Autumn J. Hadac, Elizabeth M. Nace, Rebecca A. Russell, Stephen J. MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy |
| author_facet |
Ruiz, Autumn J. Hadac, Elizabeth M. Nace, Rebecca A. Russell, Stephen J. |
| author_sort |
Ruiz, Autumn J. |
| title |
MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy |
| title_short |
MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy |
| title_full |
MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy |
| title_fullStr |
MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy |
| title_full_unstemmed |
MicroRNA-Detargeted Mengovirus for Oncolytic Virotherapy |
| title_sort |
microrna-detargeted mengovirus for oncolytic virotherapy |
| description |
Mengovirus, a member of the Picornaviridae family, has a broad cell tropism and can cause encephalitis and myocarditis in multiple mammalian species. Attenuation has been achieved by shortening the polycytidine tract in the 5′ noncoding region (NCR). A poly(C)-truncated strain of mengovirus, vMC24, resulted in significant tumor regression in immunocompetent BALB/c mice bearing syngeneic MPC-11 plasmacytomas, but the associated toxicities were unacceptable. To enhance its safety profile, microRNA target sequences complementary to miR-124 or miR-125 (enriched in nervous tissue), miR-133 and miR-208 (enriched in cardiac tissue), or miR-142 (control; enriched in hematopoietic tissues) were inserted into the vMC24 NCRs. The microRNA-detargeted viruses showed reduced replication and cell killing specifically in cells expressing the cognate microRNAs, but certain insertions additionally were associated with nonspecific suppression of viral fitness in vivo. In vivo toxicity testing confirmed that miR-124 targets within the 5′ NCR suppressed virus replication in the central nervous system while miR-133 and miR-208 targets in the 3′ NCR suppressed viral replication in cardiac tissue. A dual-detargeted virus named vMC24-NC, with miR-124 targets in the 5′ NCR and miR-133 plus miR-208 targets in the 3′ NCR, showed the suppression of replication in both nervous and cardiac tissues but retained full oncolytic potency when administered by intratumoral (106 50% tissue culture infectious doses [TCID50]) or intravenous (107 to 108 TCID50) injection into BALB/c mice bearing MPC-11 plasmacytomas. Overall survival of vMC24-NC-treated tumor-bearing mice was significantly improved compared to that of nontreated mice. MicroRNA-detargeted mengoviruses offer a promising oncolytic virotherapy platform that merits further development for clinical translation. |
| publisher |
American Society for Microbiology |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810567/ |
| _version_ |
1613558747546779648 |