CRISPR cancer therapy doesn't kill healthy cells

Monday, 14 March, 2022

CRISPR cancer therapy doesn't kill healthy cells

A new cancer therapy called CINDELA, developed by researchers from South Korea’s Institute for Basic Science (IBS), employs CRISPR-Cas9 to kill cancer cells without affecting normal tissues. The breakthrough has been published in the journal PNAS.

Radiation and chemotherapy destroy cancer cells by producing DNA double-strand breaks. Unfortunately, since both treatments target DNA in normal cells as well as cancer cells, indiscriminate killing of healthy cells and side effects are unavoidable when using these treatments. Scientists have long been searching for a method to selectively target only cancer cells without affecting normal cells; now, researchers at the IBS Center for Genomic Integrity (CGI) have combined the concepts of cancer genomics and CRISPR-Cas9 (commonly called genetic scissors) to propose a potential solution.

Cancer genomics projects have found that regardless of their origins, most cancer cells accumulate many mutations including small insertion/deletion (InDel) of several nucleotides, single nucleotide changes and large chromosomal aberrations. Meanwhile, CRISPR-Cas9 can be used to make DNA double-strand breaks in a sequence-specific manner. The CGI researchers proposed that by using CRISPR-Cas9 to produce DNA double-strand breaks at cancer-specific mutations that only exist in cancer cells, they could trigger cell death in cancer cells without affecting normal cells.

First, the researchers confirmed that enzyme-driven DNA double-strand breaks using CRISPR were able to induce cell deaths in cancer similar to physical or chemical breaks driven by radiation or chemotherapies, respectively. Then, they performed bioinformatics analysis to identify unique InDel mutations in several different cancer cell lines, including breast, colon, leukaemia and glioblastoma, which are not found in normal cells. Based on this information, they successfully made CRISPR-Cas9 reagents targeting those mutations.

The scientists named this new treatment CINDELA, which stands for ‘cancer-specific InDel attacker’, and confirmed that it was able to selectively kill cancer cells without affecting normal cells. It was discovered that CINDELA-driven cancer cell death was dependent on the number of DNA double-strand breaks created by CRISPR-Cas9; for example, a CINDELA reagent which induced 50 breaks in the DNA was much better at killing cancer cells than the reagent that induced only 10 breaks.

In addition to cancer cell line experiments, the researchers conducted further animal studies to verify CINDELA’s efficacy in living organisms. To do so, tumour cells (colon and lung cancer) were derived from patients and were xenografted into mice. It was found that the CINDELA treatment can substantially suppress the growth of tumours in these mice. Notably, since CINDELA targets InDel mutations which are generated as by-products during tumorigenesis, CINDELA can be applied to treat most tumours.

“We believe CINDELA can become a novel therapeutic application for cancer treatments as personalised and precision medicine for all cancer patients without severe side effects,” said CGI Director Kyungjae Myung. The researchers have already started applying this technology in tumours directly taken from patients, with research groups having expertise in the relevant technologies, such as gene delivery, companion diagnostic platform and cancer genomics.

One obstacle that the researchers had during all these experiments was the delivery of CINDELA reagents to tumours. Although the researchers could achieve significant tumour growth inhibition using a high titre of the virus to deliver the CRISPR in mice, as of yet this may not be enough to directly treat human patients. However, such an obstacle is one of the major issues in the current CRISPR-Cas9 field. Researchers believe that in the near future, the development of new delivery systems will eventually help establish the CINDELA cancer treatment technology in cancer patients.

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