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.
Although second-generation replication-conditional herpes simplex virus type 1 (HSV-1) vectors defective for both ribonucleotide reductase (RR) and the virulence factor gamma(1)34.5 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.
Kanai
Ryuichi
R
Molecular Neurosurgery Laboratory, Department of Neurosurgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Tomita
Hideyuki
H
Hirose
Yuichi
Y
Ohba
Shigeo
S
Goldman
Steven
S
Okano
Hideyuki
H
Kawase
Takeshi
T
Yazaki
Takahito
T
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy / Q000821:virology; D009419:Nerve Tissue Proteins / Q000235:genetics; D050130:Oncolytic Virotherapy; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins / Q000235:genetics; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics
C491297:MSI1 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1