Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence

R. Kanai, H. Tomita, A. Shinoda, M. Takahashi, S. Goldman, Hideyuki Okano, T. Kawase, T. Yazaki

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

G207 is a conditionally replicating derivative of herpes simplex virus type1 (HSV-1) engineered with deletions of both ICP34.5 loci and a lacZ insertion disabling the ICP6 gene. G207 exhibits an efficient oncolytic activity in vitro and in vivo, yet minimal toxicity in normal tissue, and is now in clinical trial for malignant glioma. According to the results of clinical trials, however, although G207 was proved to be safe, the efficacy was not so impressive. Deletion of the ICP34.5 gene coding for virulence made G207 extremely safe, but it markedly reduced the cytotoxicity mediated by HSV-1. To enhance the therapeutic efficacy of G207 without diminishing its safety, we used a defective vector containing Musashi1 promoter/ICP34.5, with G207 as helper virus. P/ musashi1 was functional selectively in human glioma cell lines (U87MG, U251, T98G) in this study and dvM345 showed a much higher therapeutic efficacy both in culture and in the in vivo glioma model, than G207 alone, without diminishing its favorable toxicity profile. These results suggest that transcriptional regulation of ICP34.5 by P/musashi1 can be used to target HSV-1 virulence toward gliomas while maintaining the desirable neuroattenuated phenotype.

Original languageEnglish
Pages (from-to)106-116
Number of pages11
JournalGene Therapy
Volume13
Issue number2
DOIs
Publication statusPublished - 2006 Jan

Fingerprint

Glioma
Virulence
Simplexvirus
Clinical Trials
Helper Viruses
Gene Deletion
Therapeutics
Phenotype
Safety
Cell Line
Genes

Keywords

  • G207
  • Glioma
  • Musashi 1
  • Oncolytic herpes vector
  • Transcriptional control

ASJC Scopus subject areas

  • Genetics

Cite this

Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence. / Kanai, R.; Tomita, H.; Shinoda, A.; Takahashi, M.; Goldman, S.; Okano, Hideyuki; Kawase, T.; Yazaki, T.

In: Gene Therapy, Vol. 13, No. 2, 01.2006, p. 106-116.

Research output: Contribution to journalArticle

Kanai, R. ; Tomita, H. ; Shinoda, A. ; Takahashi, M. ; Goldman, S. ; Okano, Hideyuki ; Kawase, T. ; Yazaki, T. / Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence. In: Gene Therapy. 2006 ; Vol. 13, No. 2. pp. 106-116.
@article{8604f58937974dc4a6ca0e20526f7a4b,
title = "Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence",
abstract = "G207 is a conditionally replicating derivative of herpes simplex virus type1 (HSV-1) engineered with deletions of both ICP34.5 loci and a lacZ insertion disabling the ICP6 gene. G207 exhibits an efficient oncolytic activity in vitro and in vivo, yet minimal toxicity in normal tissue, and is now in clinical trial for malignant glioma. According to the results of clinical trials, however, although G207 was proved to be safe, the efficacy was not so impressive. Deletion of the ICP34.5 gene coding for virulence made G207 extremely safe, but it markedly reduced the cytotoxicity mediated by HSV-1. To enhance the therapeutic efficacy of G207 without diminishing its safety, we used a defective vector containing Musashi1 promoter/ICP34.5, with G207 as helper virus. P/ musashi1 was functional selectively in human glioma cell lines (U87MG, U251, T98G) in this study and dvM345 showed a much higher therapeutic efficacy both in culture and in the in vivo glioma model, than G207 alone, without diminishing its favorable toxicity profile. These results suggest that transcriptional regulation of ICP34.5 by P/musashi1 can be used to target HSV-1 virulence toward gliomas while maintaining the desirable neuroattenuated phenotype.",
keywords = "G207, Glioma, Musashi 1, Oncolytic herpes vector, Transcriptional control",
author = "R. Kanai and H. Tomita and A. Shinoda and M. Takahashi and S. Goldman and Hideyuki Okano and T. Kawase and T. Yazaki",
year = "2006",
month = "1",
doi = "10.1038/sj.gt.3302636",
language = "English",
volume = "13",
pages = "106--116",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Enhanced therapeutic efficacy of G207 for the treatment of glioma through Musashi1 promoter retargeting of γ34.5-mediated virulence

AU - Kanai, R.

AU - Tomita, H.

AU - Shinoda, A.

AU - Takahashi, M.

AU - Goldman, S.

AU - Okano, Hideyuki

AU - Kawase, T.

AU - Yazaki, T.

PY - 2006/1

Y1 - 2006/1

N2 - G207 is a conditionally replicating derivative of herpes simplex virus type1 (HSV-1) engineered with deletions of both ICP34.5 loci and a lacZ insertion disabling the ICP6 gene. G207 exhibits an efficient oncolytic activity in vitro and in vivo, yet minimal toxicity in normal tissue, and is now in clinical trial for malignant glioma. According to the results of clinical trials, however, although G207 was proved to be safe, the efficacy was not so impressive. Deletion of the ICP34.5 gene coding for virulence made G207 extremely safe, but it markedly reduced the cytotoxicity mediated by HSV-1. To enhance the therapeutic efficacy of G207 without diminishing its safety, we used a defective vector containing Musashi1 promoter/ICP34.5, with G207 as helper virus. P/ musashi1 was functional selectively in human glioma cell lines (U87MG, U251, T98G) in this study and dvM345 showed a much higher therapeutic efficacy both in culture and in the in vivo glioma model, than G207 alone, without diminishing its favorable toxicity profile. These results suggest that transcriptional regulation of ICP34.5 by P/musashi1 can be used to target HSV-1 virulence toward gliomas while maintaining the desirable neuroattenuated phenotype.

AB - G207 is a conditionally replicating derivative of herpes simplex virus type1 (HSV-1) engineered with deletions of both ICP34.5 loci and a lacZ insertion disabling the ICP6 gene. G207 exhibits an efficient oncolytic activity in vitro and in vivo, yet minimal toxicity in normal tissue, and is now in clinical trial for malignant glioma. According to the results of clinical trials, however, although G207 was proved to be safe, the efficacy was not so impressive. Deletion of the ICP34.5 gene coding for virulence made G207 extremely safe, but it markedly reduced the cytotoxicity mediated by HSV-1. To enhance the therapeutic efficacy of G207 without diminishing its safety, we used a defective vector containing Musashi1 promoter/ICP34.5, with G207 as helper virus. P/ musashi1 was functional selectively in human glioma cell lines (U87MG, U251, T98G) in this study and dvM345 showed a much higher therapeutic efficacy both in culture and in the in vivo glioma model, than G207 alone, without diminishing its favorable toxicity profile. These results suggest that transcriptional regulation of ICP34.5 by P/musashi1 can be used to target HSV-1 virulence toward gliomas while maintaining the desirable neuroattenuated phenotype.

KW - G207

KW - Glioma

KW - Musashi 1

KW - Oncolytic herpes vector

KW - Transcriptional control

UR - http://www.scopus.com/inward/record.url?scp=29944447647&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29944447647&partnerID=8YFLogxK

U2 - 10.1038/sj.gt.3302636

DO - 10.1038/sj.gt.3302636

M3 - Article

VL - 13

SP - 106

EP - 116

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 2

ER -