Anti-cancer binary system activated by bacteriophage HK022 integrase

Elias, Amer; Gritsenko, Natasha; Gorovits, Rena; Spector, Itay; Prag, Gali; Yagil, Ezra; Kolot, Mikhail

doi:10.18632/oncotarget.25512

Cited by 7 publications

(3 citation statements)

References 60 publications

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“…This will help identify and manipulate critical residues that are important for the att sites’ recognition and binding. Additionally, the correction of targeted mutated genes by Int-based RMCE approach in tissue cultures ( ex vivo ) and mice models ( in vivo ) will be performed using systemic treatment ( 72 , 79 ). Such an approach of mutated genes correction with the appropriate sequence may favor cured cells and even show increased efficiencies.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the use of Integrase-based binary system as an anti-cancer treatment did not show any broad toxicity effects as known in alternative technologies in the lungs and spleen of the healthy mice. TUNEL assay that detects double strand breaks, did not show any DNA damage in the healthy mice tissue biopsies taken 45 days after systemic injections (twice a week) ( 79 ). These findings strengthen our claim that HK022 Int-based gene therapy is a safe strategy.…”

Section: Discussionmentioning

confidence: 99%

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HK022 bacteriophage Integrase mediated RMCE as a potential tool for human gene therapy

Elias

Kassis

Elkader

et al. 2020

Nucleic Acids Research

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HK022 coliphage site-specific recombinase Integrase (Int) can catalyze integrative site-specific recombination and recombinase-mediated cassette exchange (RMCE) reactions in mammalian cell cultures. Owing to the promiscuity of the 7 bp overlap sequence in its att sites, active ‘attB’ sites flanking human deleterious mutations were previously identified that may serve as substrates for RMCE reactions for future potential gene therapy. However, the wild type Int proved inefficient in catalyzing such RMCE reactions. To address this low efficiency, variants of Int were constructed and examined by integrative site-specific recombination and RMCE assays in human cells using native ‘attB’ sites. As a proof of concept, various Int derivatives have demonstrated successful RMCE reactions using a pair of native ‘attB’ sites that were inserted as a substrate into the human genome. Moreover, successful RMCE reactions were demonstrated in native locations of the human CTNS and DMD genes whose mutations are responsible for Cystinosis and Duchene Muscular Dystrophy diseases, respectively. This work provides a steppingstone for potential downstream therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HK022 bacteriophage Integrase mediated RMCE as a potential tool for human gene therapy

Elias

Kassis

Elkader

et al. 2020

Nucleic Acids Research

Self Cite

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“…Once inside the cancer cells, the recombinase removes the transcription terminator sequence flanked by attR and attL recombination sites and activates the expression of DTA. This could result in less DTA expression in normal cells and lower non-specific toxicity (Elias et al, 2018).…”

Section: Expression Of Dt Under the Control Of Specific Promotersmentioning

confidence: 99%

Targeted Diphtheria Toxin-Based Therapy: A Review Article

Shafiee¹,

Aucoin²,

Jahanian-Najafabadi³

2019

Front. Microbiol.

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Cancer remains one of the leading causes of death worldwide. Conventional therapeutic strategies usually offer limited specificity, resulting in severe side effects and toxicity to normal tissues. Targeted cancer therapy, on the other hand, can improve the therapeutic potential of anti-cancer agents and decrease unwanted side effects. Targeted applications of cytolethal bacterial toxins have been found to be especially useful for the specific eradication of cancer cells. Targeting is either mediated by peptides or by protein-targeting moieties, such as antibodies, antibody fragments, cell-penetrating peptides (CPPs), growth factors, or cytokines. Together with a toxin domain, these molecules are more commonly referred to as immunotoxins. Targeting can also be achieved through gene delivery and cell-specific expression of a toxin. Of the available cytolethal toxins, diphtheria toxin (DT) is one of the most frequently used for these strategies. Of the many DT-based therapeutic strategies investigated to date, two immunotoxins, OntakTM and TagraxofuspTM, have gained FDA approval for clinical application. Despite some success with immunotoxins, suicide-gene therapy strategies, whereby controlled tumor-specific expression of DT is used for the eradication of malignant cells, are gaining prominence. The first part of this review focuses on DT-based immunotoxins, and it then discusses recent developments in tumor-specific expression of DT.

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