Closing the RNA Loop Holds Promise for More Stable, Effective RNA Therapies

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• Liezel Labios- [email protected]

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• RNA Therapeutics
• Circular RNAs

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New methods to shape RNA molecules into circles could lead to more effective and long-lasting therapies, shows a study by researchers at the University of California San Diego. The advance holds promise for a range of diseases, offering a more enduring alternative to existing RNA therapies, which often suffer from short-lived effectiveness in the body.

The work was published Aug. 26 in Nature Biomedical Engineering.

RNA molecules have emerged as powerful tools in modern medicine. They can silence genes through small interfering RNAs (siRNAs) or serve as templates for making therapeutic proteins, as seen with messenger RNAs (mRNAs). Unlike gene editing technologies, which make permanent changes to DNA, RNA therapies offer a temporary but highly targeted approach.

However, one major challenge is RNAs do not last long in the body, which limits their effectiveness. The concept of circular RNAs (cRNAs) have gained traction as a solution to this challenge. Circular RNAs, unlike their linear counterparts, have a closed-loop structure that renders them more resistant to degradation. The problem is that existing methods for creating circular RNAs are complex and inefficient.

To overcome these hurdles, researchers led by Prashant Mali, a professor in the Shu Chien-Gene Lay Department of Bioengineering at UC San Diego, developed two new methods for producing circular RNAs that are simple and scalable. One method occurs inside cells using a naturally occurring protein called RtcB, to splice RNA strands into loops. The other method, in contrast, uses a type of bacterial enzyme known as group II introns to form circular RNAs outside of cells. The researchers also developed simple purification steps that significantly boost the yield of circular RNAs. These advancements mean that circular RNAs can be produced with greater ease and quantities than previously possible.

The circular RNAs were tested in heart muscle cells and neurons. They displayed enhanced stability and biological activity, outperforming traditional linear RNAs in both cell types. These findings suggest that circular RNAs could be beneficial in treating conditions that affect the heart and nervous system.

Next, researchers are working to extend these studies into additional in vivo settings.

Paper: "Robust genome and cell engineering via in vitroand in situcircularized RNAs." Co-authors include Michael Tong, Nathan Palmer, Amir Dailamy, Aditya Kumar, Hammza Khaliq, Sangwoo Han, Emma Finburgh, Madeleine Wing, Camilla Hong, Yichen Xiang, Katelyn Miyasaki, Andrew Portelli, Joseph Rainaldi, Amanda Suhardjo, Sami Nourreddine, and Ester J. Kwon, UC San Diego; and Wei Leong Chew, Genome Institute of Singapore.

This work was supported by UC San Diego Institutional Funds, the National Institutes of Health (R01HG012351, OT2OD032742, R01NS131560, U54CA274502, DP2NS111507), Department of Defense (W81XWH-22-1-0401), a Longevity Impetus Grant from Norn Group, a UC San Diego Gene Therapy Initiative Grant (GTI-2024-018), and an American Heart Association Postdoctoral Fellowship (AHA 916973). This publication includes data generated at the UC San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (S10 OD026929). This work was performed in part at the San Diego Nanotechnology Infrastructure (SDNI) at UC San Diego, a member of the National Nanotechnology Coordinated Infrastructure, which is supported by the National Science Foundation (grant ECCS-2025752).

Disclosures: Authors have filed patents based on this work. Prashant Mali is a scientific co-founder of Shape Therapeutics, Navega Therapeutics, Pi Bio, Boundless Biosciences, and Engine Biosciences. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. The remaining authors declare no competing interests.