Tuesday, March 28, 2023

Study identifies risks in use of CRISPR therapeutics

The researchers caution: “The CRISPR genome editing method is very effective, but not always safe. Sometimes the truncated chromosomes do not recover and genomic stability is compromised – which can promote cancer in the long run ” A new study from TAU identifies risks in the use of CRISPR therapeutics – an innovative, Nobel-prize-winning method that involves cleaning and editing DNA, which is already associated with cancer, liver and intestinal diseases and genetic syndromes. employed for the treatment of conditions such as Examining the effect of this technique on T-cells – the white blood cells of the immune system, the researchers detected loss of genetic material in a significant percentage – up to 10% of the treated cells. They show that such damage can lead to genome instability, which can lead to cancer.

The study was led by Drs from the School of Neurobiology, Biochemistry and Biophysics at TAU’s WISE Faculty of Life Sciences and the Doton Center for Advanced Therapies, a collaboration between Tel Aviv Sourasky Medical Center (Ichilov) and Tel Aviv University. Adi Barzel, and TAU’s Faculty of Medicine and Edmund J. From the Safra Center for Bioinformatics, Dr. Asaf Madi and Dr. by Uri Ben-David. The findings were published in the leading scientific journal Nature Biotechnology.

The researchers explain that CRISPR is an important technique for editing DNA-cleaving DNA sequences at certain locations to remove unwanted segments, or alternatively to insert repair or beneficial segments. Developed nearly a decade ago, this technology has already proven to be impressively effective in treating a wide variety of diseases – cancer, liver disease, genetic syndromes, and more. The first approved clinical trial so far to use CRISPR was conducted at the University of Pennsylvania in 2020, when researchers applied the method to T-cells — the white blood cells of the immune system. Taking T-cells from a donor, they expressed an engineered receptor targeted to cancer cells, using CRISPR to destroy the gene coding for the original receptor—which would otherwise be able to attack T-cells in the recipient’s body. -could cause cells.

In the current study, the researchers sought to examine whether the potential benefits of CRISPR therapeutics could be offset by the risks posed by cleavage, considering that broken DNA is not always repairable.

Dr. Ben-David and his research colleague Eli Reuveni explain: “The genome in our cells is often broken down by natural causes, but it is usually able to repair itself without causing any damage. Still, sometimes A certain chromosome is unable to bounce back, and large sections, or even entire chromosomes, are lost. Such chromosomal disruptions can destabilize the genome, and we often see this in cancer cells. Thus, CRISPR therapeutics, in which DNA is intentionally cleaved as a means of treating cancer, can, in extreme scenarios, actually promote malignancies.”

To investigate the extent of the potential damage, the researchers repeated the 2020 Pennsylvania experiment, clearing the genome of T-cells at the exact same location — chromosomes 2, 7, and 14 (out of the 23 pairs of chromosomes in the human genome). . Using a state-of-the-art technique called single-cell RNA sequencing, they analyzed each cell separately and measured the expression levels of each chromosome in each cell.

In this way, a significant loss of genetic material was found in some cells. For example, when chromosome 14 was truncated, about 5% of cells showed little or no expression of this chromosome. When all chromosomes were cleaved together, damage increased, with 9%, 10%, and 3% of cells unable to repair breaks in chromosomes 14, 7, and 2, respectively. The three chromosomes differed, however, in the extent of damage they sustained.

Dr. Maddy and her student Ella Goldschmid explained: “Single-cell RNA sequencing and computational analysis enabled us to obtain very accurate results. We found that the cause of the difference in damage was the precise location of the cleaving on each of the three chromosomes. Overall, our findings suggest that more than 9% of T-cells genetically edited with the CRISPR technology had lost a significant amount of genetic material. Such loss may lead to genome instability, which can lead to cancer. can promote.”

Based on their findings, the researchers caution that extra care should be taken when using CRISPR therapeutics. They also propose alternative, low-risk, methods for specific medical procedures, and recommend further research into two types of potential solutions: reducing the production of damaged cells or identifying the damaged cells and treating the patient. Removing them before delivering the material.

Dr. Barzel and his PhD student Alessio Nahmad concluded: “Our intention in this study was to shed light on the potential risks in the use of CRISPR therapeutics. We did this when we were aware of the substantial benefits of the technology. In fact, in other studies , we have developed CRISPR-based treatments, including a promising therapy for AIDS. We have also established two companies – one using CRISPR and the other deliberately avoiding this technology. Effective technology advances, as well as time warns of its potential dangers. It may sound like a contradiction, but as scientists we are quite proud of our approach, because we believe it to be a part of science. The gist is: We don’t ‘choose sides’. We examine both the positive and negative aspects of an issue and look for answers.”


Journal Reference:

Nahmad, E. and others. (2022) Recurrent aneuploidy in primary human T cells after CRISPR-Cas9 cleavage. Nature Biotechnology. doi.org/10.1038/s41587-022-01377-0.

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