Researchers have issued a warning about the use of ‘gene editing’ after finding the cells of early human embryos are often unable to repair breaks in their DNA caused by editing.
Gene editing techniques – in particular CRISPR-Cas9 – have been used to develop therapies for a range of conditions including sickle cell disease. However, genetic editing of human embryos is currently banned in most countries.
Dr Nada Kubikova from University of Oxford, who led the study, says their findings could have important implications for the proposed use of gene editing techniques to remove serious inherited diseases from embryos.
Dr Kubikova presented the research to the 39th annual meeting of the European Society of Human Reproduction and Embryology (ESHRE), Copenhagen, Denmark. She said: “Gene editing has the potential to correct defective genes, a process that usually involves first breaking and then repairing the DNA strand. Our new findings provide a warning that commonly used gene editing technologies may have unwanted and potentially dangerous consequences if they are applied to human embryos.”
She warns using CRISPR-Cas9 in early human embryos “carries significant risks”.
“We have found that the DNA of embryo cells can be targeted with high efficiency, but unfortunately this rarely leads to the sort of changes needed to correct a defective gene,” she said.
“More often, the strand of DNA is permanently broken, which could potentially lead to additional genetic abnormalities in the embryo.”
Gene editing has begun to be used in children and adults with diseases caused by gene mutations such as cystic fibrosis, cancer and sickle cell disease.
However, because CRISPR-Cas9 has the potential to create changes in the human genome that would be passed down the generations, and because of questions around its safety, most countries ban its use in embryos.
In an ethically approved study, Dr Kubikova and her colleagues fertilised donated eggs with donated sperm using intracytoplasmic sperm injection (ICSI) to create 84 embryos. They used CRISPR-Cas9 in 33 of the embryos, to create DNA double-strand breaks. The remaining 51 embryos were kept as controls.
“We used CRISPR to target areas of the DNA that don’t contain any genes,” said Dr Kubikova. “This is because we wanted to learn what is always true about how CRISPR affects embryo cells and their DNA, and not be distracted by changes caused by disrupting a particular gene.”
They found all the cells of the body have highly efficient mechanisms for repairing damage affecting their DNA. In most cases, the ends of broken DNA strands were reconnected quickly.
“This is very important, as the persistence of unrepaired DNA damage stops cells working properly and can be lethal,” said Dr Kubikova.
The most common way that cells repair DNA is ‘non-homologous end joining’, where the two ends of a break are glued together, which often creates additional changes to the DNA sequence. Another way cells can repair a break in the DNA is by ‘homology directed repair’, where a template is used to ensure the repair results in the correct DNA sequence. Homology directed repair is the technique required to correct mutations that cause disease.
The researchers detected alterations at the targeted DNA sites in 24 out of 25 embryos, which indicated that CRISPR is highly efficient in the cells of human embryos.
However, only 9% of targeted sites were repaired using the clinically useful process of homology directed repair, while 51% of broken DNA strands underwent non-homologous end joining, producing mutations where the strands were reconnected.
The remaining 40% of broken DNA strands failed to be repaired. The unrepaired breaks in the DNA strands eventually led to large pieces of chromosomes being lost or duplicated. Abnormalities of this type affect the viability of embryos and if affected embryos were transferred to the uterus and produced a baby, they would carry a risk of serious congenital abnormalities.
“Our study shows that homology directed repair is infrequent in early human embryos and that, in the first few days of life, the cells of human embryos struggle to repair broken DNA strands,” said Dr Kubikova.
“While the results caution against the use of genome editing in human embryos, there were some positive findings, suggesting that risks can be lowered and the ability to successfully remove mutations can be increased by modifying the way in which genome editing is undertaken. This offers hope for future improvements to the technology.
“On average, only about a quarter of the embryos created using IVF succeed in producing a baby. Half of them stop developing in the laboratory before they can be transferred to the womb. The inability of embryos to efficiently repair DNA damage, revealed by this study, may explain why some IVF embryos fail to develop. This understanding may lead to improved IVF treatments.”
The research team is to look for new ways to protect early embryos from DNA damage, which could lead to potential improvements in fertility treatments. They also plan to explore more gentle methods of gene editing that avoid breakage of the DNA strands, which embryos might find easier to cope with.
Kubikova N, Esbert M, Titus S, Coudereau C, Savash M, Fagan J, Scott R, Wells D. (2023) “O-075: Deficiency of DNA double-strand break repair in human preimplantation embryos revealed by CRISPR-Cas9”. Presentation at 39th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), Copenhagen, Denmark.
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