Termination of Fusion Genes by CRISPR Cas-9, A Novel Therapeutic Option

Researchers have successful induced cancer cell death in murine models of sarcoma and leukaemia by cutting fusion genes with the aid of CRISPR. CRISPR-Cas9 served an invaluable role as a gene-editing tool to induce cell death in cancerous cells containing fusion genes. The technique led to the elimination of tumour cells in cell lines and murine models of Ewing’s sarcoma and chronic myeloid leukaemia (CML). The researchers suggest that, their approach could lead to novel highly specific cancer therapies, able to destroy cancer cells without affecting healthy ones.

Chromosomal rearrangement during cell division leads to formation of fusion genes. They are the product of two DNA fragments, often originating from completely different chromosomes joining, leading to the development of interaction between two genes that were never intended to interact. This sort of erroneous formation can be lethal to the cell, if the disadvantages are high thus leading to the termination of the fusion gene. Although some fusion genes are able to express beneficial traits such as reproductive or survival capabilities that allow the carrier cell to multiply, forming a tumour. An instance is BCR-ABL which causes CML.

Formation of fusion genes by chromosomal rearrangements forms the basis of childhood sarcomas and leukaemias. Fusion genes express abundance in 20% of cancers including breast cancer, prostate cancer, lung cancer and brain tumours. One outstanding advantage of Fusion genes is that they occur only in cancer tissues this makes them potential target for therapies.

CRISPR Cas-9 is an ideal tool for editing fusion genes. This is because it can be programmed to target specific sequences of the genome and subsequently cut and paste DNA fragments to induce modifications in a regulated pattern. The study was able to use CRISPR Cas-9 to eliminate tumour cells by cutting out the fusion gene promoting tumour development. Cell lines and mouse models of Ewing’s sarcoma and CML were used for these experiments.

Although this is the first application of CRISPR in fusion gene editing, its use was successful compared with earlier less effective methods that required addition of a DNA sequence that induces cell death at the junction between the two fused genes, but this method of introducing foreign sequences proved to be very ineffective at eliminating tumours.

Instead of introducing a sequence, CRISPR was used to make cuts in the introns at either end of the fusion gene: the idea is that in trying to repair those breaks on its own, the cell will join the cut ends which will result in the complete elimination of the fusion gene located in the middle. Fusion genes are essential for the survival of tumour cells, so this repair automatically causes the cell to die.

Future studies will analyse the safety and efficiency of this approach. These steps are essential to determine the possibility of transforming this approach into a potential clinical treatment.

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