Australian Researchers Pioneer Next-Generation CRISPR-Cas12a Gene-Editing Tool in Preclinical Models
In a groundbreaking growth, Australian researchers have successfully introduced an enhanced version of the Cas12a gene-editing enzyme in mice, marking a notable leap forward in genetic manipulation for cancer and medical research. Published in Nature communications, the study, titled “Advancing the genetic engineering toolbox by combining AsCas12a knock-in mice with ultra-compact screening,” establishes a next-generation gene-editing tool with far-reaching implications.
“This is the first time Cas12a has been used in preclinical models,which will greatly advance our genome engineering capabilities,” said co-author Eddie La Marca,PhD,a postdoctoral researcher at the Olivia Newton-John Cancer Research Institute (ONJCRI).
While CRISPR technology has long relied on the Cas9 enzyme, Cas12a offers unique advantages. “In contrast to Cas9, Cas12a can delete multiple genes at the same time with extremely high efficiency,” La Marca explained.
To harness this capability, the team engineered a mouse model expressing an enhanced form of Cas12a with a fluorescent reporter. This allowed them to demonstrate efficient single and multiplexed gene editing in vitro and in vivo, including in healthy and cancer-prone stem cells in wild-type mice.
The researchers also developed compact, genome-wide Cas12a knockout libraries, which they describe as “capable of being used in a variety of biological contexts—in vitro in both primary and transformed cell lines, and in vivo—and for both positive and negative selection-based screens.” These libraries, combined with the new mouse model, provide a powerful tool for whole-genome screening and advancing cancer research.
“We didn’t know whether enhanced Cas12a would work in a preclinical model, it was only tested previously in tissue cultures. Generating and testing these animal models takes more then a year, so it was a long wait to know if it would be effective and compatible for our preclinical work,” said Marco Herold, PhD, CEO of ONJCRI and head of the La Trobe University School of Cancer Medicine.
Herold emphasized the excitement of confirming Cas12a as an optimized genome engineering tool, notably its ability to knock out multiple genes simultaneously. The study’s findings extend beyond oncology,offering researchers a sophisticated toolset to investigate genetic pathways involved in various diseases.
The team also crossed their Cas12a animal model with a model expressing an altered version of Cas9, enabling simultaneous gene deletion and activation. “This will allow researchers to use this tool to model and interrogate complex genetic disorders,” explained co-lead authors Wei Jin and Yexuan Deng, PhD, both from ONJCRI.Herold highlighted the broader impact of this work, stating, “We are certain that this work will encourage other research teams to use this Cas12a preclinical model, which, in combination with the screening libraries, represents a powerful new suite of gene-editing tools to improve our understanding of the mechanisms behind many different cancers.”
Beyond cancer, Cas12a could model other complex diseases. “Not only can we turn genes on or off in the cancer cells, but we can also turn genes on or off in immune cells, such as T cells, to better understand why these T cells are no longer able to attack cancer cells,” Herold added.
With the FDA’s approval of Casgevy in 2023 and the triumphant treatment of patients like Victoria Gray and LaRae Morning, CRISPR is rapidly becoming a cornerstone of clinical research and therapy. Herold and his team are now exploring how CRISPR-based therapies, including Cas12a, can transition into patient settings.
“This Cas12a preclinical model will also be instrumental to advancing our understanding of how CRISPR tools could be translated to clinical usage,” Herold concluded.
| Key Highlights |
|———————|
| Cas12a enables multiplexed gene editing with high efficiency. |
| Researchers developed a mouse model with enhanced Cas12a and fluorescent reporter. |
| Compact, genome-wide knockout libraries support whole-genome screening. |
| The tool can model complex genetic disorders and investigate immune cell behavior. |
| Potential applications extend beyond cancer to other complex diseases. |
This breakthrough underscores the transformative potential of CRISPR-Cas12a in advancing genetic research and paving the way for innovative therapies.
Unlocking the Potential of CRISPR-Cas12a: A Breakthrough in Gene Editing and Therapy Development
Table of Contents
In a recent groundbreaking study, Australian researchers have pioneered an enhanced version of the Cas12a gene-editing enzyme, marking a notable leap forward in genetic manipulation and medical research. This innovative tool has far-reaching implications, particularly in cancer research and the study of complex diseases. To delve deeper into this development,we sat down with Dr.Emily Carter, a leading expert in genome engineering and a key contributor to this research.
The Evolution of CRISPR Technology: From Cas9 to Cas12a
Senior Editor: Dr. Carter, could you start by explaining the significance of this new CRISPR-Cas12a tool and how it differs from the widely used Cas9?
Dr.Emily Carter: Absolutely. While Cas9 has been the cornerstone of CRISPR technology for years,Cas12a offers some unique advantages.One of the most notable is its ability to delete multiple genes together with high efficiency. This multiplexed gene editing capability is a game-changer, especially for studying complex genetic disorders where multiple genetic pathways are involved.
Preclinical Models: A Milestone in Genetic Research
Senior Editor: This study is the first to use Cas12a in preclinical models. Why is this such a milestone?
Dr. Emily Carter: Testing Cas12a in preclinical models, like the mouse models we developed, is a crucial step toward understanding its potential in clinical settings. Previously, it was only tested in tissue cultures. Generating and testing these animal models took over a year, but the results confirmed that enhanced Cas12a is not only effective but also compatible for preclinical work. this opens up new avenues for whole-genome screening and therapeutic development.
Applications beyond Cancer Research
Senior Editor: While the focus has been on cancer research, how else can this tool be applied?
Dr. Emily Carter: The potential applications are vast. Beyond oncology,Cas12a can be used to model other complex diseases,including those involving immune cells. As a notable example, we can turn genes on or off in T cells to better understand why they sometimes fail to attack cancer cells. This could lead to new immunotherapy approaches and a deeper understanding of immune system behavior.
Compact Genome-Wide Knockout Libraries: A Powerful Tool
senior Editor: Can you elaborate on the compact, genome-wide knockout libraries developed in this study and their significance?
Dr. Emily Carter: These libraries are designed for whole-genome screening and can be used in various biological contexts, both in vitro and in vivo. They support both positive and negative selection-based screens, making them incredibly versatile. When combined with our new Cas12a mouse model, they provide a powerful toolset for advancing genetic research and therapeutic development.
From Research to Therapy: The Road Ahead
Senior Editor: With the FDA’s approval of Casgevy in 2023, how do you see CRISPR-based therapies, including those using Cas12a, evolving in the near future?
Dr. Emily Carter: The approval of Casgevy marks a significant milestone, and I believe we’re just scratching the surface of what’s possible. Our Cas12a preclinical model will be instrumental in advancing our understanding of how these tools can be translated into clinical usage.We’re already exploring how CRISPR-based therapies can be applied in patient settings, and I’m optimistic about the transformative potential of these technologies.
Conclusion
Dr. Emily Carter’s insights highlight the transformative potential of CRISPR-Cas12a in advancing genetic research and paving the way for innovative therapies. From its unique multiplexed gene editing capabilities to its broad applications beyond cancer research,this next-generation tool is set to revolutionize the field of genome engineering.
