Ancient RNA-Guided System Could Simplify Delivery of Gene-Editing Therapies

Researchers at MIT have unearthed an ancient RNA-guided system in bacteria that could revolutionize the delivery of gene-editing therapies. This system, discovered in bacteria, offers a more compact and precise alternative to the commonly used CRISPR-Cas9 system. The findings, published in the journal Cell, suggest that this newly characterized system, named OMEGA (Obligate Mobile Element Guided Activity), could overcome some of the significant hurdles in delivering gene-editing tools to specific cells and tissues within the human body.

CRISPR-Cas9, while groundbreaking, faces challenges in delivery due to its large size, which limits its ability to efficiently penetrate cell membranes and reach target locations. OMEGA, being significantly smaller, presents a promising solution. “It’s smaller than CRISPR, and that gives it some advantages for delivery,” says Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT, a member of the Broad Institute of MIT and Harvard, and an investigator at the McGovern Institute for Brain Research at MIT. “There is still a lot of work to do, but this is an exciting first step.”

The OMEGA system consists of a protein called IscB and a guide RNA. These components work together to target and cut specific DNA sequences. The research team demonstrated that OMEGA could be programmed to target specific genes in human cells grown in the lab. Moreover, they showed that OMEGA could be packaged into adeno-associated viruses (AAVs), commonly used vectors for gene therapy, and delivered into cells.

One of the key advantages of OMEGA lies in its evolutionary history. The researchers believe that OMEGA evolved from transposable elements, also known as “jumping genes,” which are mobile DNA sequences capable of moving around the genome. This origin suggests that OMEGA may possess inherent mechanisms for efficient delivery and integration into DNA, making it particularly well-suited for gene-editing applications.

“This is an exciting discovery because it shows us that there are many other programmable systems out there that we can potentially harness for biomedical applications,” says Soumya Kannan, a postdoc in Zhang’s lab and one of the lead authors of the study. The team is now focused on further characterizing OMEGA, optimizing its activity, and exploring its potential for treating various genetic diseases.

The researchers also identified several different versions of the OMEGA system in various bacterial species, indicating that this system is widespread and diverse. This diversity opens up possibilities for engineering OMEGA systems with tailored properties for specific gene-editing tasks.

While still in the early stages of development, OMEGA holds immense potential for advancing gene-editing therapies. Its compact size, efficient delivery, and evolutionary origins make it a compelling alternative to CRISPR-Cas9, paving the way for more effective and accessible treatments for genetic diseases.