The CRISPR technology has the ability to fix the genetic flaw that causes the immune disorder known as chronic granulomatous disease. However, researchers have discovered that there is a possibility of unintentionally causing other genetic issues.
CRISPR’s cutting-edge molecular tools hold the promise to change the way we treat genetic conditions. They are designed to fix specific faulty parts of the genome. Unfortunately, there’s a downside: in certain situations, the repairs can result in new genetic problems, as highlighted in cases of chronic granulomatous disease. This finding was shared by a group of basic science researchers and clinicians from the ImmuGene clinical research program at the University of Zurich (UZH).
Chronic granulomatous disease is an uncommon inherited condition, affecting approximately one in 120,000 individuals. It weakens the immune system, leaving patients more vulnerable to severe and potentially fatal infections. This condition is caused by a deletion of two base letters in the DNA sequence of the NCF1 gene, which prevents the production of a crucial enzyme complex needed for immune defense against bacteria and fungi.
How CRISPR works…
The research team successfully used the CRISPR system to add the missing letters into the DNA at the appropriate locations. They conducted their experiments on immune cell cultures that shared the genetic defect found in chronic granulomatous disease patients. “This is a hopeful result for applying CRISPR technology to rectify the mutation that causes this condition,” commented Janine Reichenbach, professor of somatic gene therapy at the University Children’s Hospital Zurich and the Institute for Regenerative Medicine at UZH.
… but unfortunately, it has its flaws
Interestingly, some of the cells that were repaired began to show additional defects. Whole sections of the chromosome where the repairs occurred were missing. This is due to the unique genetic structure of the NCF1 gene: it exists three times on the same chromosome, once as an active gene and twice as pseudogenes. These pseudogenes, which are structurally identical to the defective NCF1 gene, are not typically utilized for forming the enzyme complex.
CRISPR’s cutting tools cannot differentiate between the gene versions, leading to potential multiple cuts on the chromosome—both on the active NCF1 gene and the pseudogenes. When these DNA parts are stitched back together, significant segments may be left misaligned or absent. The potential medical implications are uncertain and, in severe cases, could lead to conditions like leukemia. “This necessitates caution in the clinical application of CRISPR technology,” warns Reichenbach.
Looking for a safer approach
To reduce the risks, the research group explored various alternative strategies, including modified versions of CRISPR components. They also investigated the use of protective elements designed to lower the chances of the genetic scissors cutting the chromosome in multiple places at once. Sadly, none of these strategies could entirely eliminate the unwanted side effects.
“This study sheds light on both the exciting possibilities and the difficulties of CRISPR-based therapies,” noted co-author Martin Jinek, a professor at the UZH Department of Biochemistry. He emphasized that the findings offer important information for developing gene-editing therapies for chronic granulomatous disease and other genetic disorders. “However, more technological improvements are necessary to enhance the safety and efficacy of this method in the future.”
