Australian scientists have made a significant breakthrough in cancer research by establishing a novel gene-editing tool that has the potential to revolutionize how we model and interrogate human diseases. A team of researchers from the Olivia Newton-John Cancer Research Institute (ONJCRI), WEHI, and Genentech, a member of the Roche Group, has developed an advanced pre-clinical model that harnesses the power of a new genome-engineering enzyme, Cas12a.
This groundbreaking work, which has been detailed in a recent paper published in Nature Communications, marks the first time Cas12a has been used in pre-clinical disease models. The Cas12a enzyme is a next-generation tool in the gene-editing field, providing enhanced capabilities over its predecessor, Cas9, which has been the most widely used enzyme in CRISPR-based experiments for nearly a decade.
What is Cas12a, and Why Does it Matter?
Cas enzymes are crucial for gene-editing experiments because they allow researchers to cut specific segments of DNA or RNA. In the context of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), these enzymes are the molecular scissors that enable targeted modifications of the genome. CRISPR technology has already made significant strides in cancer research and holds promise for advancing clinical applications in patients.
While Cas9 has been the tool of choice for gene editing, researchers have identified Cas12a as a powerful alternative with distinct advantages. Unlike Cas9, which can typically modify one gene at a time, Cas12a allows for the deletion of multiple genes simultaneously with extremely high efficiency. This ability to manipulate several genes at once gives scientists a more versatile approach to modeling complex diseases, particularly cancers, which are often driven by multiple genetic mutations.
Creating the Next-Generation Pre-Clinical Model
The team of researchers, led by Dr. Eddie La Marca (Postdoctoral Researcher at ONJCRI and WEHI), successfully generated a Cas12a-enhanced pre-clinical model. This model, which uses a mouse model engineered to express Cas12a, is the first of its kind and provides a more refined tool for exploring genetic changes in diseases like lymphoma. In their research, the team was able to use the Cas12a-compatible mouse whole-genome CRISPR “libraries” to identify genes responsible for accelerating lymphoma growth.
These genome-wide CRISPR libraries are a powerful tool in cancer research because they enable researchers to screen large sets of genes to determine which ones play critical roles in disease progression. By using Cas12a to manipulate these genes, the team was able to gain a deeper understanding of how mutations contribute to the development of lymphoma, a type of cancer that affects the lymphatic system.
This research not only sheds light on the specific genetic drivers of lymphoma but also highlights the broader potential of Cas12a in studying other complex diseases. The pre-clinical model developed by the team could be used to explore the genetic underpinnings of a variety of cancers and other genetic disorders, making it an invaluable tool for future studies.
Multiplexed Gene Editing for Complex Disease Models
The power of Cas12a lies not only in its ability to delete multiple genes at once but also in its compatibility with other gene-editing tools. The research team was able to combine Cas12a with other genome-engineering techniques to allow for multiplexed gene manipulation—the simultaneous deletion, activation, or modification of multiple genes in a single experiment.
Co-lead authors Ms. Wei Jin and Dr. Yexuan Deng (both from ONJCRI and WEHI) elaborated on the significance of this development, stating, “We have also crossed our Cas12a animal model with a model that expresses an altered version of Cas9, allowing us to both delete and activate different genes simultaneously. This will allow researchers to use this tool to model and interrogate complex genetic disorders.”
By enabling the simultaneous manipulation of genes with multiple editing tools, the Cas12a model paves the way for more accurate and comprehensive disease models. These advanced models will allow scientists to better understand the genetic interactions that drive diseases like cancer, and in turn, contribute to the development of more effective therapeutic strategies.
Shaping the Future of Cancer Research
The development of the Cas12a pre-clinical model has far-reaching implications for cancer research. According to Professor Marco Herold, CEO of ONJCRI and Head of the La Trobe University School of Cancer Medicine, the new gene-editing tool offers a unique opportunity to enhance our understanding of cancer mechanisms. “We are certain that this work will encourage other research teams to use this Cas12a pre-clinical model, which, in combination with the screening libraries, is a powerful new suite of gene-editing tools to improve our understanding of the mechanisms behind many different cancers.”
Professor Herold’s team is also focused on advancing the clinical application of gene-editing technologies. They are working on developing methods to administer CRISPR-based therapies to patients. The ability to accurately model cancer through tools like the Cas12a pre-clinical model is critical in progressing toward the clinical use of CRISPR in cancer treatment.
This work is especially important given the limitations of current cancer therapies. Traditional treatments such as chemotherapy and radiation often come with severe side effects and limited efficacy, particularly in advanced stages of the disease. Gene-editing tools like Cas12a could help develop more precise, targeted therapies that address the underlying genetic causes of cancer, offering patients a potentially safer and more effective treatment option.
Overcoming the Challenges of CRISPR Technology
Despite the promise of CRISPR technology, there are still several challenges to overcome before it can be routinely used in clinical settings. One of the key hurdles is delivery—how to get the gene-editing tools into the correct cells within the body. Another challenge is ensuring the precision of the edits to avoid off-target effects, where unintended changes to the genome could occur.
In their research, the team acknowledged the importance of addressing these challenges. Professor Herold emphasized, “This Cas12a pre-clinical model will also be instrumental in advancing our understanding of how CRISPR tools could be translated to clinical usage.” By refining our ability to manipulate genes with high precision, scientists hope to unlock new therapeutic avenues for treating genetic diseases, including cancer.
A New Era for Gene-Editing Tools
The establishment of the Cas12a pre-clinical model represents a major step forward in the world of gene editing and cancer research. By offering an enhanced version of genome-engineering, researchers now have a more efficient tool to dissect the complex genetics of cancer and other diseases. This work builds on the success of earlier Cas9-based research but opens new doors for more advanced and accurate disease modeling.
As research teams continue to explore the potential of Cas12a and other CRISPR-based tools, the ultimate goal remains clear: to make these technologies viable options for treating cancer patients in the near future. With advancements in gene-editing technology, the future of cancer treatment is bright, and this research is laying the foundation for a new era of precision medicine.
Reference: Australian researchers enhance next-generation gene-editing technologies for cancer and medical research, Nature Communications (2025). DOI: 10.1038/s41467-025-56282-2