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RNA Editing: The New CRISPR?

RNA therapeutics have gained traction over the last four years, not least because of the significant global effort to create mRNA-based vaccines against COVID-19. However, the potential for the use of RNA in healthcare is not limited to this. In fact, RNA editing is now being explored as an alternative to gene editing, with experts using this method to address some of the pitfalls of tech like CRISPR. In this feature, we explore the concept of RNA editing and the benefits of using this technology over more ubiquitous tools.

What is RNA editing?

RNA editing is a process that naturally occurs within cells to edit the nucleotide sequence of RNA molecules, without changes to the precursor DNA. Although the process is relatively rare, with other modifications, such as splicing, being much more common, RNA editing is conserved across living organisms. It can lead to profound changes to the activity of the molecule, and also impacts stability and localisation.

There are two main types of RNA editing found in nature – the substitution of single bases, and the insertion or deletion of larger nucleotide sequences. Substitution editing involves the conversion of one nucleotide to another within an RNA molecule. The most common type of substitution editing is the conversion of adenosine (A) to inosine (I). Inosine is recognised as guanosine (G) during translation and can lead to changes in the protein sequence. This process is mediated by enzymes called adenosine deaminases acting on RNA (ADARs), which recognise double-stranded RNA structures and catalyse the hydrolytic deamination of adenosine to inosine. Since inosine is read as guanosine by the translational machinery, A-to-I editing can result in codon changes, leading to the incorporation of different amino acids into the protein product. Insertion/deletion editing involves the addition or removal of nucleotides from the RNA sequence. This type of editing can result in shifts in the reading frame during translation, leading to the synthesis of a completely different protein from the original RNA transcript.

Whilst RNA editing is a naturally occurring phenomenon, researchers have been keen to harness the potential of the process for therapeutic purposes. In particular, ADAR-based A-to-I editing has potential in this area, due in part to the prevalence of G-A mutations that are linked to human disease. But when we’re so used to hearing about the potential of CRISPR and other forms of DNA editing, why would we pursue RNA as a therapeutic tool?

Why edit RNA?

It seems obvious why we would choose to alter DNA because of a disease-causing mutation: correct the mutation, stop the disease. Seems easy enough, right?

But unfortunately, it’s almost never this simple. For example, CRISPR has a number of pitfalls associated with it. These include unwanted immune responses and off-target effects that often have unpredictable and dangerous consequences. In response, various teams have developed new gene editing techniques, but the potential for RNA editing remained largely untapped for a long time.

RNA editing is a desirable alternative to gene editing for several reasons. Firstly, it allows for temporary and reversible modifications to be made to RNA transcripts, providing greater flexibility in experimental settings where transient changes are desired. This is particularly advantageous when the effects of genetic modifications need to be carefully controlled or when permanent alterations to the genome are not desirable. This is particularly relevant to certain conditions such as acute pain or obesity. Secondly, RNA editing enables precise targeting of specific molecules, allowing for selective modifications without affecting the entire genome. This specificity reduces the risk of off-target effects, like those generated via CRISPR. Additionally, RNA editing can generate diverse protein isoforms, and the methods of delivery are less likely to cause unwanted immune responses.

Into the clinic

As RNA therapeutics gained recognition during the COVID-19 pandemic, there was greater interest in the potential to harness the molecule in other ways. In particular, the short-lived nature of RNA editing made it an appealing therapeutic avenue. As trust in the process grew, alongside recognition of the flaws of gene editing techniques, some RNA editing tools were approved for use in clinical trials.

Single-base substitution editing is currently being trialled to treat alpha-1 anti-trypsin deficiency (AATD), which impacts the lungs and liver. The disease is caused by an insufficient amount of a protective protein known as alpha-1 anti-trypsin (AAT), which plays a crucial role in mitigating organ damage from environmental factors such as smoking and air pollution. In December 2023, Wave Life Sciences announced that they were exploring the use of a single-base RNA editor to treat the disease, which is typically caused by single point mutations, after successful results had been obtained in mice.

In addition, an approach known as RNA exon editing has also recently been approved for use in human trials. Exon editing takes advantage of the cells own splicing machinery to replace entire faulty exons and restore wild type function. In January 2024, Ascidian Therapeutics gained approval to trial their exon editor to treat Stargardt disease and other retinopathies.

Will RNA editing replace CRISPR?

It may seem that RNA editing has everything you could want from your molecular toolkit. But as with all technology, it also has its drawbacks. The transient nature of the technology may be beneficial in some cases, but a permanent change can be desirable, for example in some monogenic disorders. The real drawback of RNA editing, however, lies in its complexity. RNA processing is intricate, and understanding the interplay between RNA editing and other events involved in the translation of RNA into protein will be key to uncovering the real potential, and risks, of this technique.

Put simply, both gene editing and RNA editing techniques have their merits. At the moment, gene editing seems to be coming out on top – but is this just because we have had more time to explore and refine the technology? Either way, it is becoming clear that there are more options out there to treat genetic diseases than we thought there were even 10 years ago, and as human trials continue, we should only see more therapies reach the clinic.

References and further reading

Booth BJ., Nourreddine S., Katrekar D., et al. RNA editing: Expanding the potential of RNA therapeutics. Mol Ther. 2023;31(6):1533-1549. doi:10.1016/j.ymthe.2023.01.005

Lenharo, M. 2024. Move over, CRISPR: RNA-editing therapies pick up steam. Available online at: https://www.nature.com/articles/d41586-024-00275-6

Reardon, S. 2020. Step aside CRISPR, RNA editing is taking off. Available online at: https://www.nature.com/articles/d41586-020-00272-5

Slotkin, W., Nishikura, K. Adenosine-to-inosine RNA editing and human disease. Genome Med 5, 105 (2013). https://doi.org/10.1186/gm508


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