A study at Karolinska Institutet in Sweden has revealed that CRISPR-Cas9 gene editing could favor mutations in the most common cancer-causing gene. What does it mean for the first CRISPR therapy trials in humans?

CRISPR-Cas9 has taken the life sciences field by storm, making gene editing simpler and faster than ever. Although CRISPR-Cas9 gene editing was only first described in 2012, the first human trials using CRISPR as a therapy were started in China last year and Europe is due to run the first one later this year. It seems like we might have rushed into it too soon, as a new study points out that therapies using this popular gene editing tool could inadvertently cause cancer.

The research, published today in Nature Medicine, describes that the use of CRISPR-Cas9 in human cells can activate the protein p53. This protein is involved in the repair of DNA breaks and can interfere with the efficiency of CRISPR to cut DNA.

This means that when selecting cells whose DNA has been correctly modified using CRISPR, those where p53 is mutated and therefore inactive will be more likely to be selected. Given that p53 mutations are the most common genetic alteration in cancer, the process used to modify and select CRISPR-edited cells could be favoring the selection of potentially cancerous cells.

The study is not good news for CRISPR Therapeutics, a Swiss company that intends to start the first CRISPR trial in humans in Europe later this year. Its application is currently under review by the EMA, which might choose to request more data regarding the risk of inducing cancer before greenlighting the clinical trial. Just last week, the FDA put a hold on its US CRISPR trial requesting more information, which resulted in a big stock drop for CRISPR Therapeutics.

However, the results are not yet definite. “Our results were obtained in a certain cell type that is currently not used in clinical trials. Thus, it needs to be firmly established that the mechanism operates also in the cell types that are actually used,” says Bernhard Schmierer, researcher at Karolinska Institutet and one of the authors of the study.

Last year, a study showing that CRISPR-Cas9 resulted in off-target genetic modifications made companies in the space take a big hit. However, several months later, Nature retracted the paper after multiple researchers pointed out faults in the research.

While the authors of the current study concede that their results need to be confirmed, they urge caution regarding the possibility of increasing the risk of cancer with CRISPR therapy.  

“Our main message is that more research is required, because there are some indications that certain therapeutic approaches could carry a certain risk of developing cancer,” Schmierer highlights. “It will be important that the patients and caregivers are informed of the potential side effects and can act on them, should they manifest.”

Even if it proves to be true that CRISPR therapy can increase the risk of cancer, not everything will be lost for the field. Schmierer believes that there are ways in which this issue could be circumvented.

“One would have to screen ex-vivo edited cells for p53 status before delivering them back into patients. Also, other CRISPR approaches such as base-editing, which does not require DNA breaks, would be an option to avoid these risks. These methods are as of yet not very specific, but a lot of work is being done to improve them.”

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