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Mol Ther. 2015 Jan;23(1):99-107. doi: 10.1038/mt.2014.177. Epub 2014 Sep 9.

Use of miRNA response sequences to block off-target replication and increase the safety of an unattenuated, glioblastoma-targeted oncolytic HSV.

Author information

1
1] Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Graduate Program in Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
2
Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
3
Laboratory of Oncology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
4
1] Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Tsinghua University School of Medicine, Beijing, China.
5
Department of Neurological Surgery, College of Medicine, Ohio State University, Columbus, Ohio, USA.
6
1] Division of Hematology, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, Ohio, USA [2] Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
7
1] Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA [2] Division of Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
8
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
9
Department of Neurological Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
10
1] Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA [2] Department of Neurological Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA [3] SVeB University of Ferrara, Ferrara, Italy.

Abstract

Glioblastoma multiforme (GBM) is an aggressive brain cancer for which there is no effective treatment. Oncolytic HSV vectors (oHSVs) are attenuated lytic viruses that have shown promise in the treatment of human GBM models in animals, but their efficacy in early phase patient trials has been limited. Instead of attenuating the virus with mutations in virulence genes, we engineered four copies of the recognition sequence for miR-124 into the 3'UTR of the essential ICP4 gene to protect healthy tissue against lytic virus replication; miR-124 is expressed in neurons but not in glioblastoma cells. Following intracranial inoculation into nude mice, the miR-124-sensitive vector failed to replicate or show overt signs of pathogenesis. To address the concern that this safety feature may reduce oncolytic activity, we inserted the miR-124 response elements into an unattenuated, human receptor (EGFR/EGFRvIII)-specific HSV vector. We found that miR-124 sensitivity did not cause a loss of treatment efficiency in an orthotopic model of primary human GBM in nude mice. These results demonstrate that engineered miR-124 responsiveness can eliminate off-target replication by unattenuated oHSV without compromising oncolytic activity, thereby providing increased safety.

PMID:
25200130
PMCID:
PMC4426800
DOI:
10.1038/mt.2014.177
[Indexed for MEDLINE]
Free PMC Article

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