Researchers have made CRISPR both more precise and far safer. Their breakthrough could pave the way for curing hereditary conditions such as chronic granulomatous disease – with the prospect that a single genetic intervention may eventually suffice.
The aim is simple: to give people a single treatment that will eliminate a disease they have had all their lives.
One example is chronic granulomatous disease, a hereditary immune deficiency in which white blood cells fail to function properly, leaving people vulnerable to repeated bacterial infections.
In principle, the defective gene behind the disease can already be repaired today – but the technique is still not safe enough for people.
That may soon change. Researchers have refined CRISPR gene-editing technology, making it more precise and with a far smaller margin of error.
“We want to use CRISPR technology to repair people’s disease-causing genes, but the tools still need refining. We are therefore making CRISPR safer and bringing it closer to clinical use. Our findings are relevant not only for people with chronic granulomatous disease but also for people with blood disorders and genetic diseases more broadly,” says Jacob Giehm Mikkelsen, Professor and lead researcher behind a series of new CRISPR studies at the Department of Biomedicine, Aarhus University, Denmark.
Jacob Giehm Mikkelsen also served as a member of the Danish Council on Ethics from 2019 to 2025.
The research has been published in Nature Communications.
The dream: repairing genes directly inside the body
There are several ways to correct defective genes and thereby cure disease.
One approach is to take out blood cells, repair the genes in the laboratory and then return the cells to the body.
If this is done with blood stem cells, the repaired stem cells will go on producing new blood cells that were previously defective but can now function normally.
The research team has refined the technique for editing disease genes in blood stem cells, but the ultimate goal is to repair the genes directly inside the body without having to remove the cells.
A bicycle patch for DNA
Jacob Giehm Mikkelsen explains that the study focuses on a type of genetic repair that uses the body’s own natural repair mechanisms. Normally, when DNA is damaged, the cell can fix it. Here, the researchers apply the same principle – but guide the process to repair the defective gene.
To do this, several components of a genetic tool are required. First, molecular scissors (the Cas9 protein) cut a hole in the DNA.
These scissors are guided by a short piece of RNA that binds to the exact spot where the genetic error lies.
Finally, a genetic patch is needed – the correct sequence for the faulty stretch of DNA.
This patch has to overlap on both sides of the error – like a bicycle patch that not only covers the puncture but also extends a little beyond it, making the repair stable and secure.
From defective gene to functioning immune cells
Once the RNA has guided the molecular scissors to the correct spot in the gene, they cut the DNA. The cell’s own repair machinery then uses the patch to seal it again.
This results in correcting not just the break but also any nearby defects – restoring the gene’s function.
“Using this method to repair blood stem cells corrects the very cells that give rise to all blood cells. In chronic granulomatous disease, this means fixing the gene that enables stem cells to produce properly functioning phagocytes.”
Phagocytes are white blood cells that engulf and break down invading microbes.
“If these cells carry a defect in the CYBB gene, they cannot, for example, kill bacteria – and these techniques can repair this,” explains Jacob Giehm Mikkelsen.
How researchers are making genetic scissors more precise
The technique has been known for several years, but it is still not reliable enough to cure human disease.
According to Jacob Giehm Mikkelsen, stem cells can react poorly to the tools. For example, a safety gene called p53 may be triggered. Normally, it protects the cell against damage, but it can instead halt cell division or, in the worst case, make the cell die.
The new research findings are related to adjustments to the technology, making it less likely to negatively affect stem cells.
One approach the researchers use to reduce the toxicity of CRISPR technology in cells is to use fewer viruses to deliver the DNA patch for repair inside them.
The explanation is simple: large numbers of viruses put the cells under stress, so the fewer there are, the better.
When the cells’ security system sounds the alarm
Another adjustment involves the genetic scissors themselves. Normally, CRISPR cuts straight across the DNA, like slicing a rubber band in two – and this can cause errors. Now, researchers make two small cuts side by side, which makes the repair more precise and reduces the risk of DNA fragments being joined incorrectly.
This enables more controlled intervention in the DNA and reduces the risk that the cell’s own repair mechanisms will incorrectly join DNA fragments across chromosomes.
It also avoids the unwanted fusion of fragments from different chromosomes, which often happens with the original CRISPR technology.
“We are fine-tuning our tools so they repair DNA efficiently – but without the high risk of errors. That is essential before we can treat patients,” explains Jacob Giehm Mikkelsen.
From the laboratory to the patients
There is still a major leap from preclinical trials in cell cultures and mouse models to treating patients. But the new results provide crucial evidence that the technology can be refined to a level of safety that makes clinical trials feasible.
Jacob Giehm Mikkelsen is now working with other research groups to bridge this gap by exploring the possibility of using CRISPR technology to repair genes directly in the human body.
The researchers have received grants to test some of their improved genetic tools among people with genetic disorders.
Whether the first clinical target will be chronic granulomatous disease or another immune deficiency remains to be seen, says Jacob Giehm Mikkelsen.
“We have several patient groups in mind. We are still assessing what will work and what will be best for the individual patients treated. But it is clear that we are especially interested in helping those who most need treatment.”
The researchers hope their work will show that the technology can now repair genes with high efficiency.
“In addition, we hope the genetic tools will not create new problems. We must be able to prove that the treatment is safe for humans,” he concludes.
