Effective Treatment of an Orthotopic Xenograft Model of Human Glioblastoma Using an EGFR-retargeted Oncolytic Herpes Simplex Virus

Uchida, Hiroaki; Marzulli, Marco; Nakano, Kenji; Goins, William F.; Chan, Justin; Hong, Chang Sook; Mazzacurati, Lucia; Yoo, Ji Young; Haseley, Amy; Nakashima, Hiroshi; Baek, Hyunjung; Kwon, Heechung; Kumagai, Izumi; Kuroki, Masahide; Kaur, Balveen; Chiocca, E. Antonio; Grandi, Paola; Cohen, Justus B.; Glorioso, Joseph C.

doi:10.1038/mt.2012.211

Cited by 96 publications

(134 citation statements)

References 47 publications

(71 reference statements)

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“…In contrast, efficient entry of KGNE at the same MOI was observed only for CHO-EGFR cells ( Fig. 5A), consistent with our previous work (39,40). All three syn mutant viruses entered exclusively into CHO-EGFR cells (Fig.…”

Section: Introduction Of Syncytial Mutations Into An Egfr-retargeted supporting

confidence: 91%

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Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

Okubo

Uchida

Wakata

et al. 2016

J Virol

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Membrane fusion, which is the key process for both initial cell entry and subsequent lateral spread of herpes simplex virus (HSV), requires the four envelope glycoproteins gB, gD, gH, and gL. Syncytial mutations, predominantly mapped to the gB and gK genes, confer hyperfusogenicity on HSV and cause multinucleated giant cells, termed syncytia. Here we asked whether interaction of gD with a cognate entry receptor remains indispensable for initiating membrane fusion of syncytial strains. To address this question, we took advantage of mutant viruses whose viral entry into cells relies on the uniquely specific interaction of an engineered gD with epidermal growth factor receptor (EGFR). We introduced selected syncytial mutations into gB and/or gK of the EGFR-retargeted HSV and found that these mutations, especially when combined, enabled formation of extensive syncytia by human cancer cell lines that express the target receptor; these syncytia were substantially larger than the plaques formed by the parental retargeted HSV strain. We assessed the EGFR dependence of entry and spread separately by using direct entry and infectious center assays, respectively, and we found that the syncytial mutations did not override the receptor specificity of the retargeted viruses at either stage. We discuss the implications of these results for the development of more effective targeted oncolytic HSV vectors. IMPORTANCEHerpes simplex virus (HSV) is investigated not only as a human pathogen but also as a promising agent for oncolytic virotherapy. We previously showed that both the initial entry and subsequent lateral spread of HSV can be retargeted to cells expressing tumor-associated antigens by single-chain antibodies fused to a receptor-binding-deficient envelope glycoprotein D (gD). Here we introduced syncytial mutations into the gB and/or gK gene of gD-retargeted HSVs to determine whether viral tropism remained dependent on the interaction of gD with the target receptor. Entry and spread profiles of the recombinant viruses indicated that gD retargeting does not abolish the hyperfusogenic activity of syncytial mutations and that these mutations do not eliminate the dependence of HSV entry and spread on a specific gD-receptor interaction. These observations suggest that syncytial mutations may be valuable for increasing the tumor-specific spreading of retargeted oncolytic HSV vectors. Herpes simplex virus 1 (HSV-1) is an important focus of research as a common human pathogen that often causes mucocutaneous lesions. In addition, HSV has recently shown promise as a tool for the development of novel therapeutic modalities against human cancers (1).Membrane fusion is the key process required for both initial entry of the virion into cells and subsequent lateral spread of HSV-1. HSV-1 entry depends on the interaction of gD with one of its cognate receptors: herpesvirus entry mediator (HVEM), nectin-1, or 3-O-sulfated heparan sulfate (3-OS-HS) (2-4). Receptor binding triggers a conformational change in gD that in turn activates...

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Section: Introduction Of Syncytial Mutations Into An Egfr-retargeted supporting

confidence: 91%

“…Our method involves mutational detargeting of gD from its canonical receptors and retargeting by insertion of a receptor-specific singlechain antibody (scFv) (38)(39)(40). We also reported that not only direct entry but also subsequent lateral spread of the EpCAMretargeted HSV strain is strictly dependent on cellular expression of the target receptor (40).…”

mentioning

confidence: 99%

Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

Okubo

Uchida

Wakata

et al. 2016

J Virol

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“…Using this approach, Justus Cohen and Hiroaki Uchida have created vectors that are fully retargeted for preferential infection of tumor cells (Uchida et al, 2013). To further tighten the tumor selectivity of these vectors, we took advantage of naturally occurring cellular microRNAs that are highly expressed in normal tissue but completely absent in tumor cells.…”

Section: Replication-competent Vectorsmentioning

confidence: 99%

Herpes Simplex Viral Vectors: Late Bloomers with Big Potential

Glorioso

2014

Human Gene Therapy

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“…In an innovative approach, Candolfi et al [67] engineered an Ad vector encoding a GBM-specific cytotoxin by fusing a ligand specific for IL-13Rα2 (a tumor specific receptor) to Pseudomonas exotoxin and showed enhanced survival without neurotoxicity in a murine model of human GBM. The groups of Grandi and Glorioso reengineered glycoproteins on HSV including a single chain antibody to target to epidermal growth factor receptors on GBM [68].…”

Section: Virus-based Systemsmentioning

confidence: 99%

Gene Therapy for the Nervous System: Challenges and New Strategies

et al. 2014

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Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that genebased neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.

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Effective Treatment of an Orthotopic Xenograft Model of Human Glioblastoma Using an EGFR-retargeted Oncolytic Herpes Simplex Virus

Cited by 96 publications

References 47 publications

Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

Herpes Simplex Viral Vectors: Late Bloomers with Big Potential

Gene Therapy for the Nervous System: Challenges and New Strategies

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