Cells in early human embryos are unable to effectively repair the double-stranded DNA breaks made during CRISPR/Cas9-based genome editing.
This means that it could be difficult to carry out genome editing on embryos using the approach, which it had been hoped could cure genetic conditions before implantation. Scientists from the University of Oxford said that while they found it possible to target the part of the genome that needed to be edited using CRISPR/Cas9, this resulted in permanent DNA strand breaks or mutations occurring at the editing site.
Dr Nada Kubikova presented the research at the European Society of Human Reproduction and Embryology 39th Annual Meeting 2023 and said: 'CRISPR/Cas9 was remarkably efficient in targeting the DNA site. However, the majority of cells repaired the DNA break induced by CRISPR using non-homologous end joining, a process that introduces additional mutations rather than correcting existing ones.
'This would be a challenge if there were attempts to use CRISPR/Cas9 to correct inherited disorders in human embryos, as it suggests that most times when it is attempted, it will not be successful.'
Currently, people who want to conceive a baby who do not have an inherited genetic condition need to undergo preimplantation genetic testing to select embryos without a specific genetic variant, or use donor gametes. Editing the genome of affected embryos to remove potentially harmful variants before transfer to the uterus, could increase the number of embryos these intended parents have available to them.
Researchers investigated how CRISPR/Cas9-based editing behaved in embryonic cells, by targeting the non-coding parts of the genome of 33 embryos fertilised using ICSI. A further 51 embryos were kept as controls in the study which has not yet been peer-reviewed.
While CRISPR/Cas9 effectively targeted the intended loci in embryonic cells, just nine percent of breaks were found to have repaired correctly. Some had been repaired using non-homologous end joining, and 40 percent of broken DNA strands failed to be repaired at all, which can cause chromosomal abnormalities or even cell death.
Researchers did not clarify which version of Cas9 they used, which has already been shown to cause DNA breaks and unintended changes, including in embryos (see BioNews 1170).
Sarah Norcross, director of the Progress Educational Trust and commissioning editor for BioNews, who was not involved in the research said: 'Many different approaches to genome editing have been developed over the years, including different ways to use CRISPR for genome editing. Each approach has its own limitations, and refinements are constantly being made.
'We need to maintain scientific rigour and ethical rigour, both of which were conspicuously absent when Dr He Jiankui infamously established pregnancies using genome-edited human embryos' (see BioNews 977 and 1129).
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