Intravesical treatment of advanced urothelial bladder cancers with oncolytic HSV-1 co-regulated by differentially expressed microRNAs

Gene Ther. 2016 May;23(5):460-8. doi: 10.1038/gt.2016.18. Epub 2016 Feb 23.

Abstract

Urothelial bladder cancer is the most common malignancy of the urinary tract. Although most cases are initially diagnosed as non-muscle-invasive, more than 80% of patients will develop recurrent or metastatic tumors. No effective therapy exists currently for late-stage metastatic tumors. By intravesical application, local administration of oncolytic Herpes Simplex virus (oHSV-1) can provide a promising new therapy for this disease. However, its inherent neurotoxicity has been a perceived limitation for such application. In this study, we present a novel microRNA-regulatory approach to reduce HSV-1-induced neurotoxicity by suppressing viral replication in neurons while maintaining oncolytic selectivity toward urothelial tumors. Specifically, we designed a recombinant virus that utilizes differentially expressed endogenous microR143 (non-cancerous, ubiquitous) and microR124 (neural-specific) to regulate expression of ICP-4, a gene essential for HSV-1 replication. We found that expression of ICP-4 must be controlled by a combination of both miR143 and miR124 to achieve the most effective attenuation in HSV-1-induced toxicity while retaining maximal oncolytic capacity. These results suggest that interaction between miR143 and miR124 may be required to successfully regulate HSV-1 replication. Our resent study is the first proof-in-principle that miRNA combination can be exploited to fine-tune the replication of HSV-1 to treat human cancers.

MeSH terms

  • Administration, Intravesical
  • Animals
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Herpesvirus 1, Human / genetics*
  • Humans
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / therapeutic use
  • Oncolytic Virotherapy / methods
  • Oncolytic Viruses / genetics
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / therapy*
  • Urothelium / pathology
  • Virus Replication / genetics

Substances

  • MIRN124 microRNA, human
  • MIRN143 microRNA, human
  • MicroRNAs