The herpes virus (HSV-1) has never been well-liked in most circles. Hey, it’s hard to blame folks, what with all of the cold sores (or worse), for not wanting to get too close. But that may soon change as a team of scientists from The Prostate Centre at Vancouver General Hospital, is looking to upgrade HSV-1’s public image and make it an ally in the battle against cancer by harnessing a little miRNA mojo.
As they described in Clinical Cancer Research, our Canadian colleagues used endogenous miRNA-target interactions, to create a HSV-1 virus that will seek and destroy only prostate tumor cells. Because of its ability to infect, then lyse cells as it replicates, HSV-1 has auditioned for roles in gene therapy delivery, or as an oncolytic agent in cancers for some time now, but as with most cancer therapies, specificity, killing only cancer cells while leaving healthy tissue intact, is the trick. To get over the specificity hurdle, the Canadian team incorporated miRNA target sites into the 3’ UTR of an HSV-1 essential viral gene, ICP4. This really slick system creates a viral “off-switch”, controlled by miRNAs, that makes HSV-1 unable to replicate where a specific miRNA is present in healthy tissue, but still able to do its cancer-killing job when it’s not.
Next the scientists tested how their new miRNA-regulated HSV-1 system would work outside of their notebooks. To build the new viral constructs, they needed to come up with miRNAs that were present in most normal tissues, but not in the prostate tumor cells they wanted to eliminate. After consulting the literature and miRNA expression profiles they found that miR-143 and miR-145 fit the bill. Armed with their new weapons of mass tumor destruction the researchers ran a battery of experiments in mice that:
- Confirmed the addition of miR-143 and miR-145 target sequences in the 3’UTR regulates ICP4 gene expression through co-transfection studies using: Ambion® Pre-Mir™ miRNA Precursors in LNCaP cells.
- Showed that HSV-1 replication is inhibited by miRNA regulation in a dose dependant manner with Ambion® Pre-Mir™ miRNA Precursors in dose response experiments.
- Demonstrated that miRNA regulated HSV-1 selectively inhibits LNCaP tumor growth (Tumor size reduced >80%) through in vivo mouse studies.
- Found that normal tissues were protected from oncolytic viral infections by miR-143 and miR-145 after tissues from in vivo studies were analyzed for the presence of ICP4 or the viral construct.
This crafty union of miRNA regulation with the infectious, oncolytic nature of HSV-1, has provided us another nice glimpse into promising cancer therapeutics on the horizon. Keep ‘em coming.
Get all of the details from the paper at Clinical Cancer Research, August 2009
Get more info on using Ambion® Pre-Mir™ miRNA Precursors in miRNA functional studies in the Featured Product section.