A Novel Oncolytic Herpes Simplex Virus Design based on the Common Overexpression of microRNA-21 in Tumors
Journal Title: Journal of Gene Therapy - Year 2018, Vol 3, Issue 1
Abstract
Background: Recognition sequences for microRNAs (miRs) that are down-regulated in tumor cells have recently been used to render lytic viruses tumor-specific. Since different tumor types downregulate different miRs, this strategy requires virus customization to the target tumor. We have explored a feature that is shared by many tumor types, the up-regulation of miR-21, as a means to generate an oncolytic herpes simplex virus (HSV) that is applicable to a broad range of cancers. Methods: We assembled an expression construct for a dominant-negative(dn) form of the essential HSV replication factor UL9 and inserted tandem copies of the miR-21 recognition sequence (T21) in the 3’ untranslated region. Bacterial Artificial Chromosome (BAC) recombineering was used to introduce the dnUL9 construct with or without T21 into the HSV genome. Virus was produced by transfection and replication was assessed in different tumor and control cell lines. Results: Virus production was conditional on the presence of the T21 sequence. The dnUL9-T21 virus replicated efficiently in tumor cell lines, less efficiently in cells that contained reduced miR-21 activity, and not at all in the absence of miR-21. Conclusion: miR-21-sensitive expression of a dominant-negative inhibitor of HSV replication allows preferential destruction of tumor cells in vitro. This observation provides a basis for further development of a widely applicable oncolytic HSV.
Authors and Affiliations
Cohen JB
Keywords
Related Articles
- EP ID EP486925
- DOI 10.13188/2381-3326.1000007
- Views 102
- Downloads 0
Medulloblastoma Treatment using Gene Therapy
Usually initiated in cerebellum and the fourth ventricle and caused by the secondary increased intracranial pressure due to blockage of the fourth ventricle, medulloblastoma (MB) is the most common malignant brain tumo...
MicroRNA-124 Suppresses Tumor Cell Proliferation and Invasion by Targeting CD164 Signaling Pathway in Non-Small Cell Lung Cancer
MicroRNAs play critical roles in regulating gene expression andvarious cellular processes in human cancer malignant progression. Down-regulated expression of miR-124 gene has been shown to be significantly associated wit...
Molecular Physiology of G-CIMP+ Glioblastomas: Therapeutic Implications
A fundamental premise of gene therapy as it pertains to oncology is precision medicine, whereby therapeutic intervention is matched to unique vulnerabilities dictated molecular physiology of the cancer [1]. Cancers pre...
cis-Antisense RNA and Transcriptional Interference: Coupled Layers of Gene Regulation
Antisense transcription is omnipresent occurring broadly in most living organisms. Growing evidence suggests the presence of noncoding cis-antisense RNA’s that can silence gene expression. Recent studies also indicate th...
A Novel Oncolytic Herpes Simplex Virus Design based on the Common Overexpression of microRNA-21 in Tumors
Background: Recognition sequences for microRNAs (miRs) that are down-regulated in tumor cells have recently been used to render lytic viruses tumor-specific. Since different tumor types downregulate different miRs, this...