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KLIPP - a precision CRISPR approach to target structural variant junctions in cancer

Huibin Yang, Radhika Suhas Hulbatte, Alan Kelleher

    Biorxiv : the Preprint Server for Biology
    |May 22, 2023
    PubMed

    Insights

    We developed KLIPP, a CRISPR/Cas9 precision cancer therapy that targets structural variant junctions to kill cancer cells specifically. This approach demonstrated significant tumor reduction in mice, offering a transformative, individualized treatment strategy.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Gene Editing

    Background:

    • Conventional cancer therapies often cause dose-limiting normal tissue toxicity.
    • There is a need for precision cancer treatments with high specificity for tumor cells.
    • Targeting cancer-specific genetic alterations can improve therapeutic efficacy and reduce side effects.

    Approach:

    • We developed KLIPP (CRISPR/Cas9-mediated targeted endonuclease), a novel precision cancer therapy.
    • KLIPP utilizes guide RNAs to target cancer-specific structural variant junctions, recruiting two parts of a Fok1 endonuclease for activation.
    • Activated Fok1 induces DNA double-strand breaks (DSBs) specifically at targeted junctions, leading to cancer cell death.

    Key Points:

    • KLIPP demonstrated high specificity for tumor cells, independent of tumor-specific drivers.
    • In orthotopic mouse models, activating Fok1 at two targeted junctions led to tumor cell disappearance in 7/11 mice.
    • The approach induces targeted DNA double-strand breaks and subsequent cancer cell death.

    Conclusions:

    • KLIPP represents a promising precision cancer therapeutic strategy with high specificity and efficacy.
    • This approach has the potential for individualized translation to patients, offering a transformative and simplified cancer treatment.
    • Further development of KLIPP could lead to more consistent and effective cancer treatment decisions.

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