CRISPR-to-Kill (C2K)–Employing the Bacterial Immune System to Kill Cancer Cells

Głów, Dawid; Maire, Cécile L.; Schwarze, Lea Isabell; Lamszus, Katrin

doi:10.3390/cancers13246306

Cited by 6 publications

(6 citation statements)

References 43 publications

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“…In another study, there is a proposal of CRISPR-to-kill (C2K) lentiviral particles targeting highly repetitive Short Interspersed Nuclear Element-Alu sequences which has more than 15,000 matched target sites within the human genome. C2K Efficiently Inhibits growth, triggers GBM cell death, and increases radiosensitivity in patient-derived GBM cell lines (PDCL-GBM), acting as suicide triggering method against cancer cells [ 129 ]. CRISPR-induced double-strand breaks (DSBs) can be applied to induce apoptosis.…”

Section: Crispr-cas Technique Against Glioblastomamentioning

confidence: 99%

Systems Medicine for Precise Targeting of Glioblastoma

Zeng¹,

Zeng

2023

Mol Biotechnol

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Glioblastoma (GBM) is a malignant cancer that is fatal even after standard therapy and the effects of current available therapeutics are not promising due its complex and evolving epigenetic and genetic profile. The mysteries that lead to GBM intratumoral heterogeneity and subtype transitions are not entirely clear. Systems medicine is an approach to view the patient in a whole picture integrating systems biology and synthetic biology along with computational techniques. Since the GBM oncogenesis involves genetic mutations, various therapies including gene therapeutics based on CRISPR-Cas technique, MicroRNAs, and implanted synthetic cells endowed with synthetic circuits against GBM with neural stem cells and mesenchymal stem cells acting as potential vehicles carrying therapeutics via the intranasal route, avoiding the risks of invasive methods in order to reach the GBM cells in the brain are discussed and proposed in this review. Systems medicine approach is a rather novel strategy, and since the GBM of a patient is complex and unique, thus to devise an individualized treatment strategy to tailor personalized multimodal treatments for the individual patient taking into account the phenotype of the GBM, the unique body health profile of the patient and individual responses according to the systems medicine concept might show potential to achieve optimum effects.

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Section: Crispr-cas Technique Against Glioblastomamentioning

confidence: 99%

Systems Medicine for Precise Targeting of Glioblastoma

Zeng¹,

Zeng

2023

Mol Biotechnol

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“…To prevent genomic instability, if the DNA damage exceeds the potential of the cell’s DNA repair mechanisms, the p53 pathway leads to an accumulation of pro-apoptotic proteins that trigger programmed cell death (reviewed in [ 23 ]). Independently from the work presented here, other groups have recently succeeded in targeting Alu elements with CRISPR/Cas9 with the purpose of inducing cell killing [ 24 , 25 ]. By supplementing Cas9 with Alu- specific sgRNAs, they were able to efficiently kill cancer cells in proof-of-concept studies, presenting the possibility of using this method to target difficult-to-treat cancer types.…”

Section: Discussionmentioning

confidence: 99%

CRISISS: A Novel, Transcriptionally and Post-Translationally Inducible CRISPR/Cas9-Based Cellular Suicide Switch

Amberger

Grueso

Ivics

2023

IJMS

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With the ever-increasing developing rate of gene and cellular therapy applications and growing accessibility due to products receiving regulatory approval, the need for effective and reliable safety mechanisms to prevent or eliminate potentially fatal side effects is of the utmost importance. In this study, we present the CRISPR-induced suicide switch (CRISISS) as a tool to eliminate genetically modified cells in an inducible and highly efficient manner by targeting Cas9 to highly repetitive Alu retrotransposons in the human genome, causing irreparable genomic fragmentation by the Cas9 nuclease and resulting cell death. The suicide switch components, including expression cassettes for a transcriptionally and post-translationally inducible Cas9 and an Alu-specific single-guide RNA, were integrated into the genome of target cells via Sleeping-Beauty-mediated transposition. The resulting transgenic cells did not show signs of any impact on overall fitness when uninduced, as unintended background expression, background DNA damage response and background cell killing were not observed. When induced, however, a strong expression of Cas9, a strong DNA damage response and a rapid halt of cell proliferation coupled with near complete cell death within four days post-induction were seen. With this proof-of-concept study, we present a novel and promising approach for a robust suicide switch with potential utility for gene and cell therapy in the future.

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“…A recently published protocol describes a simple and effective method to produce genomic knockouts of lncRNAs [ 73 ] Trans-acting elements of oncogene expression regulation are among the listed CRISPR/Cas9 targets, such as the case of CCCTC-binding factor ( CTCF ), that creates a loop between the neurotensin ( NTS ) oncogene and an upstream enhancer sequence, promoting an NTS overexpression in uveal melanoma tumor cells [ 74 ]. It is worth mentioning a particular study [ 75 ], in which the authors switched their search for potential CRISPR/Cas9 targets from oncogenes or other sequences with an oncogenic role, to a widespread class of repeat sequences through the human genome, namely the Alu short interspersed nuclear elements (SINE) class of retrotransposons, that number approximately 3 million conserved copies in our genome [ 76 ]. By this approach, CRISPR to kill (C2K), the authors aim of generating multiple DSBs throughout the tumor genome, which would make the cancer cell impossible to recover from such an extensive degree of damage.…”

Section: Approaches For Therapeutic Genome Editing In Human Malignant...mentioning

confidence: 99%

“…The results showed that C2K managed to successfully induce cell-cycle arrest and trigger apoptosis, in addition to synergizing with radiation treatment cell growth inhibition. This system showed to be highly specific for human cells, as no similar effects were obtained on murine cells [ 75 ]. However, this study lacks experimental data that would highlight its preclinical application on in vivo glioblastoma models.…”

Section: Approaches For Therapeutic Genome Editing In Human Malignant...mentioning

confidence: 99%

“…It is worth mentioning a particular study, where the authors used CRISPR/Cas9 was used not for knocking out a gene, or two, three genes, but a highly repetitive sequence, the Alu short interspersed nuclear element (SINE), that numbers more than a million copies spread throughout the human genome. Although this simple, yet powerful CRISPR/Cas9 system was tested only on glioblastoma cells in vitro with positive results [ 75 ], it introduces a new concept of “dirty CRISPR/Cas9”, that aims to cut the tumor genome to such an extent that it cannot recover from such extensive damage. In addition, further combination with DNA damaging agents can have a devastating effect on the tumor cell.…”

Section: Concluding Remarks and Future Perspectivementioning

confidence: 99%

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Genome Editing Approaches with CRISPR/Cas9 for Cancer Treatment: Critical Appraisal of Preclinical and Clinical Utility, Challenges, and Future Research

Chira

Nuțu

Isacescu

et al. 2022

Cells

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The increasing burden on human malignant diseases became a major concern for healthcare practitioners, that must deal with tumor relapse and the inability to efficiently treat metastasis, in addition to side effects. Throughout the decades, many therapeutic strategies have been employed to improve the clinical outcomes of cancer patients and great efforts have been made to develop more efficient and targeted medicines. The malignant cell is characterized by genetic and epigenetic modifications, therefore targeting those specific drivers of carcinogenesis is highly desirable. Among the genome editing technologies, CRISPR/Cas9 stood as a promising candidate for cancer treatment alternatives, due to its low complexity design. First described as a defense mechanism of bacteria against invading foreign DNA, later it was shown that CRISPR components can be engineered to target specific DNA sequences in a test tube, a discovery that was awarded later with the Nobel Prize in chemistry for its rapid expansion as a reliable genome editing tool in many fields of research, including medicine. The present paper aims of describing CRISPR/Cas9 potential targets for malignant disorders, and the approaches used for achieving this goal. Aside from preclinical studies, we also present the clinical trials that use CRISPR-based technology for therapeutic purposes of cancer. Finally, a summary of the presented studies adds a more focused view of the therapeutic value CRISPR/Cas9 holds and the associated shortcomings.

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CRISPR-to-Kill (C2K)–Employing the Bacterial Immune System to Kill Cancer Cells

Cited by 6 publications

References 43 publications

Systems Medicine for Precise Targeting of Glioblastoma

Systems Medicine for Precise Targeting of Glioblastoma

CRISISS: A Novel, Transcriptionally and Post-Translationally Inducible CRISPR/Cas9-Based Cellular Suicide Switch

Genome Editing Approaches with CRISPR/Cas9 for Cancer Treatment: Critical Appraisal of Preclinical and Clinical Utility, Challenges, and Future Research

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