Augmented therapeutic efficacy of an oncolytic herpes simplex virus type 1 mutant expressing ICP34.5 under the transcriptional control of musashi1 promoter in the treatment of malignant glioma

Ryuichi Kanai, Hideyuki Tomita, Yuichi Hirose, Shigeo Ohba, Steven Goldman, Hideyuki Okano, Takeshi Kawase, Takahito Yazaki

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Although second-generation replication-conditional herpes simples virus type 1 (HSV-1) vectors defective for both ribonucleotide reductase (RR) and the virulence factor γ134.5 have been proven safe through a number of animal experiments and clinical trials, their therapeutic efficacy was also markedly reduced. To overcome this situation, we concentrated on the use of a tumor-specific promoter in this study, to express ICP34.5 selectively in malignant glioma cells. As a molecular marker for malignant glioma, we focused on the neural RNA-binding protein, Musashi1. On the basis of the results of defective vector dvM345, as reported previously, we created, via homologous recombination, a novel HSV-1 vector termed KeM34.5, which expresses ICP34.5 under the transcriptional control of the musashi1 gene promoter (P/musashi1). Cytotoxicity mediated by KeM34.5 was significantly enhanced in human glioma cell lines (U87MG, U87MG-E6, U251, and T98G), resulting in an approximately 2-log increase in viral yield, compared with its parental vector G207. This virus also showed much higher therapeutic efficacy in the in vivo glioma model, while maintaining the desirable neuroattenuated phenotype. These results suggest that oncolytic HSV-1 expressing ICP34.5 under the transcriptional control of the musashi1 gene promoter could be a promising therapeutic agent for the treatment of malignant glioma.

Original languageEnglish
Pages (from-to)63-73
Number of pages11
JournalHuman Gene Therapy
Volume18
Issue number1
DOIs
Publication statusPublished - 01-01-2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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