A once forgotten technology, RNA editing has been gaining traction as a treatment for genetic conditions given its key advantages over CRISPR gene editing.
Since CRISPR-Cas9 gene editing was first reported in 2012, its promise of making gene editing faster, cheaper, and easier than ever before led to an explosion in the number of publications referring to this gene editing technology.
An increasing number of research labs and companies are aiming to translate CRISPR gene editing into therapies for genetic diseases. However, further research has unveiled that there are more limitations to using CRISPR-Cas9 to cure diseases than initially expected. For example, the technology has been reported to introduce off-target changes to the DNA, raising concerns about its safety.
In the meantime, RNA editing has emerged as an alternative to CRISPR technologies, getting a lot of attention from researchers and industry. RNA editing allows scientists to make changes in the molecules that carry the instructions needed to produce proteins, without changing the original DNA code.
One common method of RNA editing consists of using an enzyme called adenosine deaminase acting on RNA (ADAR), which uses a guide RNA sequence to identify the target RNA molecules and change one of its building blocks, or ‘bases’. This can be used to repair point mutations in the RNA instructions that would otherwise result in a damaged or even absent protein.
Overcoming major limitations of CRISPR
Although RNA editing was first described in the late 1980s, its therapeutic potential wasn’t explored until 1995, when the US biotech Ribozyme Pharmaceuticals started researching it within the context of muscular dystrophy.
However, the concept of therapeutic RNA editing was quickly forgotten, only to be ‘rediscovered’ nearly two decades later by German chemist Thorsten Stafforst from the University of Tübingen and the biologist Joshua Rosenthal of the Marine Biology Laboratory in Chicago, USA.
For Stafforst and Rosenthal, the timings of their respective publications on RNA editing in 2012 and 2013 were inconvenient. The news of CRISPR gene editing being possible in mammalian cells created such a buzz in the scientific community, that Stafforst himself experienced great difficulty in getting his results published. Who would need to edit RNA if we could already manipulate the DNA?
It took the FDA and EMA approval of the RNA interference drug patisiran in 2018 to revive the attention on the therapeutic potential of RNA editing. Since then, this technology seems to be experiencing momentum as it becomes increasingly clear that it might have some major advantages over CRISPR gene editing to treat human diseases.
First of all, ADAR is an enzyme naturally present in the human body. This means that for RNA editing therapies, only the guide RNA would need to be delivered. In contrast, CRISPR gene editing requires the delivery of the Cas9 protein in addition to an RNA guide. This protein is bulky and is obtained from microorganisms, which leaves it at risk of being recognized as foreign by the immune system.
An additional advantage is that guide RNAs belong to a class of drugs called antisense oligonucleotides, of which there are already six FDA-approved molecules available to treat a range of diseases. With the safety of guide RNA already established, the approval of RNA editing treatments could be significantly accelerated.
One of the strongest advantages of RNA editing is that changes to the RNA are only temporary. Concerns regarding irreversibly modifying human DNA would therefore cease with RNA editing. Even if off-target effects occur, they would disappear with time as the drug is eventually broken down and stops exerting its effects.
Recognizing the potential of RNA editing
The biotech industry is increasingly recognizing the potential of RNA editing, with a growing number of companies and startups working in this field. Among them are ProQR, a Dutch company that focuses on treating rare genetic disorders that cause blindness; and Vico Therapeutics in Belgium, looking into spinocerebellar ataxia and Huntington’s disease.
Overseas, there is Edit Force in Japan, working in neurodegenerative conditions and cancer. In the US we find Shape Therapeutics and Locana; the latter develops treatments for motor-neuron disease and Huntington’s disease.
While these companies are raising big amounts of funding, their technology is still in the early stages. Some of them, like ProQR and Shape Therapeutics, have promising results in studies with mice, but none has tested the technology in humans yet. Although the process of RNA editing has been known since the 1980s, there are still some challenges to resolve before the technology can be taken to clinical trials.
Firstly, RNA is comparably unstable as a molecule and delicate to handle. Researchers are working on finding a delivery system that can direct the guide RNA to its target location while protecting it from degradation. Secondly, as with the RNA guides used for CRISPR gene editing, the RNA guides for RNA editing treatments can potentially cause an immune reaction, which needs to be ruled out individually before their approval.
Thirdly, RNA editing enzymes are very specific regarding which RNA bases they exchange. This means the technology is limited to a few kinds of changes, which, in turn, limits the number of conditions that it can treat, making it less attractive as a research tool when compared to CRISPR-Cas9. It will take some time until protein engineering allows us to modify RNA editing enzymes involved to expand the types of conversion they can perform.
Still, RNA editing seems to hold major promise to tackle diseases for which there is no cure available yet. Studies in mice showed results supporting RNA editing as a potentially powerful tool for genetic diseases like muscular dystrophy.
Before this technology becomes clinically viable, however, its efficiency will need to be optimized and its safety tested. At this point, it is not possible to say when, or if, RNA editing will make it to the clinic. But the latest research developments and the interest of the industry in RNA editing indicate that someday soon, these therapies might be able to help patients suffering from a wide range of diseases.
The author of this article wishes to remain anonymous
Images from Elena Resko and Shape Therapeutics