miRNAs Targeting ICP4 and Delivered to Susceptible Cells in Exosomes Block HSV-1 Replication in a Dose-Dependent Manner

Wang, Lei; Chen, Xiaoqing; Zhou, Xusha; Roizman, Bernard; Zhou, Grace Guoying

doi:10.1016/j.ymthe.2018.02.016

Cited by 25 publications

(23 citation statements)

References 47 publications

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“…The miRNA sequences targeting mouse CTLA-4 were designed as described previously [32]. The synthesized DNA fragments encoding the miRNAs were digested with BamHI and XhoI restriction enzymes and cloned into the corresponding sites of pcDNA6.2-GW/EmGFP-miR-neg control plasmid (Invitrogen).…”

Section: Plasmids Expressing Mir-ctla-4mentioning

confidence: 99%

“…The procedures for production, purification and employment of exosomes containing microRNAs (miRNAs) targeting specific mRNAs employed in this laboratory were described elsewhere in detail (32). Briefly: The first step was to design a series of 10 miRNAs targeting CTLA-4 and carrying published sequences that result in preferential packaging of the miRNAs into exosomes (Panel A of Figure 5) [28,30].…”

Section: Production and Characterization Of Exosomes Containing Mir-cmentioning

confidence: 99%

“…In recent years, numerous studies have shown that RNAs carrying specific nucleotide signatures are preferentially packaged in exosomes [28][29][30][31]. An example of the genetic engineering of exosomes is the significant reduction of HSV-1 replication in susceptible cells exposed to exosomes incorporating miRNA targeting the mRNA of an essential viral protein [32].…”

Section: Introductionmentioning

confidence: 99%

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Enhancement of Oncolytic Activity of oHSV Expressing IL-12 and Anti PD-1 Antibody by Concurrent Administration of Exosomes Carrying CTLA-4 miRNA

Yan¹,

Zhou²,

Chen³

et al. 2019

Immunotherapy

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Systemic administration of checkpoint inhibitors alone and especially concurrent with intratumoral administration of oncolytic herpesviruses (oHSV) has a major impact on cancer therapy marred by rare failures of healthy organs.Furthermore, tumors vary with respect to susceptibility to oncolytic effects of oHSV. Here we report the construction and properties of 3 families of oncolytic herpes simplex viruses expressing no immunomodulatory genes (T1 series), murine IL-12 (T2 series) or murine or human IL-12 and anti PD-1 antibody (T3 series). We report that insertion of the gene encoding PD-1 Ab significantly augmented the oncolytic activity of oHSV bereft of immunostimulatory genes (T1 series) or expressing IL-12 alone (T2 series). The T3 oHSV expressed IL-12, PD-1 Ab were restricted to the tumor bed whereas the induced IFN-γ accumulated to high levels both in tumor bed and in blood. Furthermore, the T3 oHSV was superior to systemic administration of IL-12 and antibody to PD-1. This report also shows that the oncolytic activity of T3 oHSV in a relatively resistant tumor was enhanced by concurrent intratumoral administration of genetically engineered exosomes carrying miRNA targeting CTLA-4 checkpoint.

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Section: Plasmids Expressing Mir-ctla-4mentioning

confidence: 99%

Section: Production and Characterization Of Exosomes Containing Mir-cmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhancement of Oncolytic Activity of oHSV Expressing IL-12 and Anti PD-1 Antibody by Concurrent Administration of Exosomes Carrying CTLA-4 miRNA

Yan¹,

Zhou²,

Chen³

et al. 2019

Immunotherapy

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“…In an earlier study, this laboratory designed a miRNA targeting a major herpes simplex virus (HSV) regulatory protein. As predicted by the nucleotide packaging signal, the miRNAs were packaged in exosomes and, upon exposure to infected cells, signi cantly reduced virus yields [21].…”

Section: Introductionmentioning

confidence: 90%

Exosomes containing miRNAs targeting HER2 synthesis and engineered to adhere to HER2 on tumor cells surface exhibit enhanced antitumor activity

Wang

Zhou

Zou

et al. 2020

Preprint

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Background: Exosomes are small, cellular membrane-derived vesicles with a diameter of 50-150 nm. Exosomes are considered ideal drug delivery systems with a wide range of applications in various diseases, including cancer. However, nonspecific delivery of therapeutic agents by exosomes in vivo remains challenging. H uman epidermal growth factor receptor 2 (HER2) is an epidermal growth factor receptor tyrosine kinase, and its overexpression is usually associated with cell survival and tumor progression in various cancers. In this study, we aim to develop novel exosomes with dual HER2-targeting ability as a nanoparticle delivery vehicle to enhance antitumor efficacy in vivo . Results: Here, we report the generation of two kinds of exosomes carrying miRNAs designed to block HER2 synthesis and consequently kill tumor cells. 293-miR-HER2 exosomes package and deliver designed miRNAs to cells to block HER2 synthesis. These exosomes kill cancer cells dependent on HER2 for survival but do not affect cells that lack HER2 or that are engineered to express HER2 but are not dependent on it for survival. In contrast, 293-miR-XS-HER2 exosomes carry an additional peptide, which enables them to adhere to HER2 on the surface of cancer cells. Consequently, these exosomes preferentially enter and kill cells with surface expression of HER2. 293-miR-XS-HER2 exosomes are significantly more effective than the 293-miR-HER2 exosomes in shrinking HER2-positive tumors implanted in mice. Conclusions: Collectively, as novel antitumor drug delivery vehicles, HER2 dual-targeting exosomes exhibit increased target-specific delivery efficiency and can be further utilized to develop new nanoparticle-based targeted therapies.

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“…The first four are involved in the regulation of viral transcription [19]. ICP4 is a transcription factor that recruits cellular complexes, including TFIID, to viral DNA to enhance transcription initiation and can also function to repress transcription of some viral genes [20]. ICP0 is an immediate early viral protein crucial in both lytic and latent HSV-1 infection [21].…”

Section: Anti-tumor Mechanism Of Oncolytic Virusmentioning

confidence: 99%

Oncolytic Herpes Simplex Virus ICP47 Deletion Reverses Tumor Immune Evasion

Cheng¹,

Wang²,

Zhang³

et al. 2018

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Herpes simplex virus (HSV) is an enveloped, double-stranded DNA virus that has been used with modification as oncolytic viruses (OVs) against a number of tumor types. OVs represent a new class of therapeutic agents that promote anti-tumour responses through a dual mechanism of action that is dependent on selective tumor cell killing and the induction of systemic anti-tumour immunity. Among OVs, HSVs preferentially replicate in and lyse cancer cells, leading to in situ autovaccination, adaptive anti-virus and anti-tumor immunity. Suppression of antitumor immunity after OV therapy has been observed and the molecular and cellular mechanisms of action are recently reported. ICP47, a small protein produced by the herpes simplex virus, is considered as an important factor in the evasion of cellular immune responses in HSV-infected cells. Therefore, reviewing the research status of ICP47 is certainly helpful to improve the anti-tumor effect of oncolytic HSVs (oHSVs). Here, this review will focus on the following contents: 1) Anti-tumor mechanism of OVs; 2) Functions of early HSV genes; 3) The mechanism of immune escape of ICP47; 4) Recombinant HSV against cancer; 5) The functional verification of ICP47 deletion. This review highlights the current understanding of recombinant HSVs against cancers.

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miRNAs Targeting ICP4 and Delivered to Susceptible Cells in Exosomes Block HSV-1 Replication in a Dose-Dependent Manner

Cited by 25 publications

References 47 publications

Enhancement of Oncolytic Activity of oHSV Expressing IL-12 and Anti PD-1 Antibody by Concurrent Administration of Exosomes Carrying CTLA-4 miRNA

Enhancement of Oncolytic Activity of oHSV Expressing IL-12 and Anti PD-1 Antibody by Concurrent Administration of Exosomes Carrying CTLA-4 miRNA

Exosomes containing miRNAs targeting HER2 synthesis and engineered to adhere to HER2 on tumor cells surface exhibit enhanced antitumor activity

Oncolytic Herpes Simplex Virus ICP47 Deletion Reverses Tumor Immune Evasion

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