The Forefront of New Gene Editing Technologies: 'Split RNA Switches' and Prime Editing
Gene editing technology has undergone phenomenal evolution over the past few years. With the advent of CRISPR-Cas9, it became possible to edit DNA as if cutting and pasting with scissors. However, even more precise and safer technologies are now being developed one after another. The 'split RNA switch' technology announced by the Center for iPS Cell Research and Application (CiRA) at Kyoto University is one of the latest achievements in this field.
Challenges faced by RNA switches
An RNA switch is an artificial RNA molecule that can turn gene expression on or off by recognizing specific biomolecules (such as microRNAs or proteins) within a cell. Various applications have been anticipated, such as selecting cells by inducing the production of drug-resistant proteins that only function in target cells, or performing genome editing only in specific cells.
However, conventional RNA switches have had a major problem called 'translational leakage.' This is a phenomenon where a small amount of protein is produced even in non-target cells. When considering medical applications, this 'slight leakage' becomes a significant safety issue.
An innovative solution utilizing protein splicing
To solve this problem, a research group led by Professor Hirohide Saito focused on a biological phenomenon discovered in yeast called 'protein splicing.' Protein splicing is a reaction in which a special protein called an 'intein' excises itself and ligates the remaining parts together.
The newly developed 'split RNA switch' cleverly utilizes this mechanism. The target protein is divided into two fragments, each controlled by a separate RNA switch. In target cells, both fragments are correctly produced and joined via the intein to become a functional protein. On the other hand, in non-target cells, the fragments produced by translational leakage bind with mutant fragments, resulting in a non-functional protein.
With this technology, the precision of cell selection has been significantly improved, and by causing the Cas9 protein to function only in specific cells, safer genome editing has become possible. Furthermore, by recognizing multiple biomolecules simultaneously, it is possible to achieve cell identification under more complex conditional settings.
Prime Editing: A technology attracting attention as a 'word processor' for DNA
As introduced in past articles, research seeking 'more natural gene editing functions, if CRISPR is artificial' is progressing.
Introduced in 2019, 'Prime Editing' is attracting attention as a technology that further enhances the precision and safety of gene editing. If conventional CRISPR-Cas9 is 'DNA scissors,' prime editing is called a 'DNA word processor.'
The greatest feature of prime editing is that it can accurately rewrite sequences at targeted positions without cutting the DNA double helix. A prime editor combines a Cas9 nickase, which cuts only one side of the double helix, with a reverse transcriptase, and can 'write' a new sequence according to the instructions of a pegRNA (prime editing guide RNA) that contains the content to be edited.
Steady steps toward clinical application
In May 2025, Prime Medicine announced positive initial data from the world's first prime editing clinical trial for patients with chronic granulomatous disease. The result, showing that neutrophil function recovered to 58% with just a single administration, demonstrates the great potential of this technology.
However, on another note, consideration must also be given to the ethical aspects of gene editing technology. As I have written in previous articles, along with technological progress, the strengthening of social acceptance and support systems will also be essential.
Future prospects and challenges
Split RNA switches and prime editing enhance the precision and safety of gene editing through different approaches. Split RNA switches improve the precision of cell selection and targeting, while prime editing enables accurate editing without cutting DNA.
These technologies have a complementary relationship, and in the future, combining them may lead to even more advanced gene therapies. For example, a strategy of accurately identifying target cells with a split RNA switch and performing prime editing only in those cells is conceivable.
However, many challenges remain for practical application. There is a mountain of problems to solve, such as improving editing efficiency, completely eliminating off-target effects, and developing efficient delivery methods into the body. There is also the current situation where legal frameworks and ethical discussions are not keeping pace with the rapid development of gene editing technology.
Summary
Gene editing technology holds the potential to revolutionize the treatment of intractable diseases. New technologies such as split RNA switches and prime editing are paving the way for safer and more precise gene therapies. The day when these technologies are utilized in actual clinical settings may not be far off.
However, at the same time, we must carefully consider not only the benefits of these technologies but also their implications. By having scientific progress and social understanding advance hand in hand, perhaps we can realize medical care that truly contributes to human well-being.
Reference Articles
o Development of the new RNA technology "Split RNA Switch" (July 1, 2025)
o Biological DNA scissors comparable to CRISPR discovered (October 15, 2023)
o A new era in Down syndrome treatment: The future opened up by CRISPR-Cas9 (February 25, 2025)
o David Liu Wins 2025 Breakthrough Prize for Base Editing and Prime Editing (2025)
o Prime Medicine Announces Breakthrough Clinical Data (May 19, 2025)