CRISPR-based gene-editing tools are being developed to correct specific defective sections of the genome to cure inherited genetic diseases, with some applications already in clinical trials.
However, there is a catch: under certain conditions, the repair can lead to large-scale deletions and rearrangements of DNA — as in the case of targeting the NCF1 gene in chronic granulomatous disease (CGD). This was reported by a team of researchers and physicians from the ImmuGene clinical research program at the University of Zurich.
Their findings have important implications not just for gene editing-based therapy, but also for CRISPR-mediated gene editing of animals and plants, where the same types of large-scale genetic damage could be triggered.
Indeed, because such editing is carried out with much less caution in non-human organisms, the likelihood of such large-scale damage occurring is hugely increased (see below on multiplexing).
The study also shows that attempts to avoid these problems by using adaptations of CRISPR gene editing technologies, such as prime and base editing, may not succeed.
This research on CGD is also only the latest in a series of studies that have repeatedly shown that different types of unintended mutations resulting from gene editing can affect the functioning of multiple gene systems, with potentially damaging consequences.
What is CGD?
CGD is a rare hereditary disease that affects about one in 120,000 people. The disease impairs the component of the immune system responsible for fighting off infections, which can be life-threatening to the patient.
One variant of CGD is caused by the absence of two letters in the DNA base unit gene sequence which codes for the NCF1 protein. This error results in the inability of blood cells known as neutrophils to produce an enzyme complex that plays an essential role in the immune defense against bacterial, yeast, and fungal infections.
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