21 August 2023

Danish researchers have developed a gene-editing approach which they say could become a treatment for fusion-driven cancers including subtypes of acute myeloid leukaemia (AML).

Researchers from Aarhus University, Denmark, used CRISPR/Cas9 to develop a gene therapy that deletes sections of genes which have become fused together, rendering these cancer-driving ‘fusion genes’ ineffective. They say although the breakthrough study focuses on blood cancer, the technology could be applied to other types of cancer driven by fusion genes.

Fusion genes are created when two chromosomes are joined together, causing cells to begin dividing uncontrollably. They showed that their technique cuts the fusion gene and stops the cancer cells from dividing.

A team led by Prof Maja Ludvigsen applied the treatment to AML cell lines in a laboratory setting. They also showed that, when cells were treated with the gene editing therapy before being inserted into mice, it reduces tumour growth, resulting in smaller tumours or none at all.

Results were published in the journal Leukemia.

“Our gene therapy seems to be extremely effective in the laboratory,” said Prof Ludvigsen. “We don’t know whether we can make the therapy effective enough to target all the cancer cells. But there is a hypothesis within the field of cancer research that, if you can target the majority of the cancer cells with a treatment, the immune system will take care of the rest.”

They hope to be able to identify the most optimal delivery method, and show their technique also works in mice that have the specific fusion-driven subtype of leukaemia.

However, the team found the gene editing technique also introduced fusion genes into normal healthy cells, which they say will need to be researched further to understand the safety of the technique.

“One of the challenges is that if we cut the DNA in a cancer cell where the chromosome is placed incorrectly, then we’ll also be cutting the same chromosome in other healthy cells,” said Prof Ludvigsen.

“Since the fusion gene is not present in healthy cells, our theory is that healthy cells can repair their DNA themselves, but naturally we have to look into this more closely.”

Prof Ludvigsen hopes clinical trials with this form of treatment could begin within five years.

 

Source:

Neldeborg S, Soerensen JF, Møller CT, Bill M, Gao Z, Bak RO, Holm K, Sorensen B, Nyegaard M, Luo Y, Hokland P, Stougaard M, Ludvigsen M, Holm CK. (2023) “Neldeborg S, Soerensen JF, Møller CT et al. Dual intron-targeted CRISPR-Cas9-mediated disruption of the AML RUNX1-RUNX1T1 fusion gene effectively inhibits proliferation and decreases tumor volume in vitro and in vivo.” Leukemia, doi: 1-10.10.1038/s41375-023-01950-9.

Link: https://www.nature.com/articles/s41375-023-01950-9

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