The CRISPR "molecular scissors" offer groundbreaking potential for treating genetic diseases by precisely targeting and correcting defective genes. However, according to findings from researchers and clinicians from the University of Zurich’s ImmuGene program, this approach carries risks, as unintended genetic defects can occur in certain conditions, including chronic granulomatous disease.

Chronic granulomatous disease is a rare inherited condition affecting approximately one in 120,000 people. It weakens the immune system, leaving patients vulnerable to severe, sometimes fatal infections. The root cause is a small genetic error—a two-base deletion in the NCF1 gene. This genetic defect hinders the production of a crucial enzyme complex needed to defend against bacteria and mold.

The research team demonstrated that the CRISPR system could insert the missing bases into the correct location within the genome. These experiments were conducted in immune cell cultures with the same genetic mutation found in chronic granulomatous disease patients. “This is a promising result for the use of CRISPR technology to correct the mutation underlying this disease,” said Janine Reichenbach, professor of somatic gene therapy at the University Children’s Hospital Zurich and the UZH Institute for Regenerative Medicine.

Interestingly, while some cells were successfully repaired, others showed new issues, including missing chromosome sections at the repair site. The cause lies in the unique structure of the NCF1 gene, which is duplicated three times on the same chromosome: once as an active gene and twice as pseudogenes. These pseudogenes mirror the defective NCF1 sequence but aren’t typically used to create the enzyme complex.

The CRISPR scissors can’t differentiate between the active gene and its pseudogenes, sometimes cutting the DNA at all three spots. When these sections reconnect, they may be misaligned or missing crucial segments. The consequences can be severe and, at worst, may contribute to leukemia. “This calls for caution when using CRISPR technology in a clinical setting,” warned Reichenbach.

To reduce these risks, the team explored alternatives, including modified CRISPR tools and protective elements to decrease the chances of cuts at multiple sites. Unfortunately, none of these adjustments fully prevented the unwanted side effects.

“This study highlights both the promising and challenging aspects of CRISPR-based therapies,” noted co-author Martin Jinek, a professor at UZH’s Department of Biochemistry. He believes this research provides essential insights into developing gene-editing treatments for chronic granulomatous disease and other genetic conditions. “However, further technological advances are needed to make the method safer and more effective in the future.”