Artificial modification of DNA has been possible for decades, but the development of CRISPR-Cas systems for genome modification marked the beginning of a new era of modern gene editing. Since the early 2010s, these tools have enabled researchers to identify and modify specific regions of the genome. Today, they have numerous research and biotechnological applications, ranging from investigating the genetic causes of disease and modifying cells to developing new therapeutic approaches.
Editing DNA has never been easier: with next-generation CRISPR-Cas systems, an increasing proportion of the genome is becoming accessible for editing, while the precision and versatility of these interventions continue to improve. One of the most precise approaches is prime editing, which enables targeted base modifications. In many cases, this method may offer improved safety by avoiding DNA double-strand breaks.
One limitation of prime editing, however, is that the Cas protein used for editing must be able to recognise the DNA at the appropriate site. This requires not only the target sequence but also the presence of a short DNA motif immediately adjacent to it, known as a PAM (protospacer adjacent motif). In Cas12a enzymes, this recognition requirement is relatively stringent, meaning that many potential targets – such as disease-associated mutations – fall outside the editable range.
Researchers from the Gene Regulation Research Group at the HUN-REN Research Centre for Natural Sciences sought to overcome this limitation. They investigated several engineered Cas12a variants, of which flexiAsCas12a proved to be the most effective. The engineered protein recognises a broader range of PAM sequences, making nearly 96% of known pathogenic human point mutations potentially targetable for editing.
Éva Varga and colleagues also demonstrated that this expanded target recognition can be incorporated into functional prime-editing systems in mammalian cells. The result is therefore more than just another Cas protein variant: it expands the range of genomic targets accessible to precise gene editing. An important next step will be to determine how efficiently and accurately the new variant can be applied across different cell types and, ultimately, in clinical settings.
The study was published in Genome Biology on 28 August 2026.
Varga, É., Gál, L., Huszár, K. et al. flexiAsCas12a and other Cas12a variants enhance the applicability of Cas12a nucleases in prime editing. Genome Biol (2026).
https://doi.org/10.1186/s13059-026-04249-x
You can also find more information here: https://bioengineer.org/flexiascas12a-and-other-variants-expand-cas12a-nuclease-applications-in-prime-editing/