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| UniSA/CCB Professor Greg Goodall, part of the team that made the landmark discovery. Photo Credit: Courtesy of University of South Australia |
Scientific Frontline: "At a Glance" Summary
- Main Discovery: Researchers identified the specific molecular mechanism responsible for actively transporting circular RNAs (circRNAs) from the cell nucleus to the cytoplasm.
- Methodology: The study mapped the export pathway and revealed that circRNAs utilize a transport mechanism resembling that of proteins, distinct from the export routes used by other forms of RNA.
- Key Data: Circular RNA possesses a closed-loop genetic structure that renders it inherently more stable and durable in the body compared to linear mRNA, which degrades rapidly.
- Significance: Understanding this transport pathway overcomes a major limitation of current RNA technology, validating circRNA as a robust platform for more effective genetic medicines.
- Future Application: These findings enable the development of a next generation of RNA therapeutics and vaccines with increased potency and longevity for treating cancer and other diseases.
- Branch of Science: Molecular Biology, Oncology, and Pharmacology.
- Additional Detail: The discovery confirms that circRNAs are not cellular byproducts but are actively transported to the cytoplasm to perform critical biological functions.
Australian scientists have made a major discovery that could underpin the next generation of RNA-based therapeutics, and lead to more potent and longer-lasting RNA-based drugs with an even wider array of potential uses.
In a paper published in the journal Nature, Peter MacCallum Cancer Centre scientists Vi Wickramasinghe and Linh Ngo and collaborator Greg Goodall at the University of South Australia and SA Pathology’s Centre for Cancer Biology, have described a new pathway that could help to overcome a major drawback of RNA-based therapeutics to date.
Currently these breakthrough therapeutics utilize mRNA – injectable genetic material that produces a desired therapeutic or vaccine effect, but they can also break down quickly once absorbed into the human body.
“It’s the linear shape of mRNA that makes it relatively unstable and lack durability inside the body and this has been a limiting factor in the potential application of RNA-based therapeutics for diseases such as cancer,” explains Dr Wickramasinghe, senior author on the paper.
“For this reason, there’s a rising interest and excitement about another more robust form of RNA – known as circular or circRNA – which has the shape of a closed loop of genetic material, making it much more durable. However key features of how circRNA operates within cells has remained a mystery - until now.”
The scientists have discovered how circular RNAs, which are made in the nucleus of cells, are actively transported out of the nucleus to their site of action in the body of the cell (the “cytoplasm”). Understanding this pathway is a major step towards harnessing circRNA for therapeutic purposes, in much the same way as mRNA.
“Intriguingly, this mechanism resembles the way some proteins are transported out of the nucleus rather than the mechanisms employed to export other types of RNA,” says Prof Goodall.
“This further cements evidence these circular RNAs, of which there are many different types, are made to carry out important functions in the cell – a contention that has been unclear for most of the circular RNAs discovered to date.
“Now this molecular mechanism is worked out, it opens up possibilities for manipulating it for beneficial outcomes such as disease therapies.”
The research is a collaboration between the Peter Mac Callum Cancer Centre and the Centre for Cancer Biology at SA Pathology and the University of South Australia, and was funded by the NHMRC, veski, the Victorian Cancer Agency and National Breast Cancer Foundation (NBCF).
Dr Wickramasinghe says when this work began in 2017 it was “purely fundamental, blue sky discovery research” and years before the COVID pandemic would herald the arrival of the world’s first mRNA vaccines.
“No one could have predicted how mRNA-based therapeutics would change medicine, nor the tremendous potential for circRNAs in underpinning the next generation of RNA-based therapeutics,” Dr Wickramasinghe says.
Published in journal: Nature
Title: Nuclear export of circular RNA
Authors: Linh H. Ngo, Andrew G. Bert, B. Kate Dredge, Tobias Williams, Vincent Murphy, Wanqiu Li, William B. Hamilton, Kirstyn T. Carey, John Toubia, Katherine A. Pillman, Dawei Liu, Jessica Desogus, Jeffrey A. Chao, Andrew J. Deans, Gregory J. Goodall, and Vihandha O. Wickramasinghe
Source/Credit: University of South Australia
Reference Number: med021424_02