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Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
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CRISPR-to-Kill (C2K)-Employing the Bacterial Immune System to Kill Cancer Cells

Dawid Głów1, Cecile L Maire2, Lea Isabell Schwarze1

  • 1Research Department, Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany.

Cancers
|December 24, 2021
PubMed

Insights

CRISPR/Cas9 technology was repurposed to create CRISPR-to-kill (C2K) vectors that induce DNA double-strand breaks (DSBs) to eliminate cancer cells. This novel gene therapy approach effectively killed human cancer cells, including treatment-resistant glioblastomas.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • CRISPR/Cas9 is a bacterial immune system targeting foreign DNA via double-strand breaks (DSBs).
  • Cancer cells often develop resistance to conventional therapies, necessitating novel treatment strategies.

Purpose of the Study:

  • To investigate the potential of CRISPR/Cas9 nucleases to induce lethal DSBs in cancer cells.
  • To develop a CRISPR-to-kill (C2K) system targeting cancer cells for gene therapy.

Main Methods:

  • Generation of CRISPR-to-kill (C2K) lentiviral particles utilizing an Alu-specific single-guide RNA (sgRNA).
  • Testing C2K-Alu-vector efficacy on human and murine cell lines, including patient-derived glioblastoma cells.
  • Assessing inhibition of cancer cell growth and resistance to irradiation.

Main Results:

  • C2K-Alu-vectors selectively induced cell death in human cancer cell lines, sparing murine cells.
  • Efficient inhibition of glioblastoma cell growth was observed, even in lines resistant to high-dose irradiation.
  • Demonstrated proof-of-concept for C2K as a treatment overcoming common resistance mechanisms.

Conclusions:

  • CRISPR/Cas9 can be engineered as a cancer cell-killing system (C2K) by inducing extensive genomic DSBs.
  • C2K targeting Alu sequences shows promise for treating cancers, including radioresistant glioblastomas.
  • C2K represents a potential novel gene therapy tool for cancer, especially when combined with tumor-targeting strategies.
Keywords:
AluCRISPR/Cas9LeGO vectorsSINEcancer gene therapyglioblastomairradiationprogrammed cell deathresistancesuicide gene

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