RNA editing has recently made significant progress as a potentially safer alternative to gene editing for treating a number of genetic diseases. In December 2023, patients were dosed in the first-ever clinical trial for an RNA editing candidate – a milestone achievement that could see RNA editing take off in the coming months.
But what exactly is RNA editing and how is it different from DNA editing?
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RNA editing versus DNA editing
DNA editing and RNA editing share the same end goal, in that they both want to alter a protein’s structure or quantity. However, unlike DNA editing, RNA editing allows scientists to make changes in the molecules that carry the instructions needed to produce proteins, without actually changing the original DNA code.
One key advantage to this is that this results in temporary effects. Although seen as a breakthrough tool, DNA editing can cause off-target effects if any mistakes are made. For example, a study in Cell showed that a CRISPR-Cas9 system designed to cleave and rejoin DNA strands to correct a mutation created the break in the wrong location or failed to repair the break about half of the time, leading to the loss of entire chromosomes. By contrast, RNA is a more forgiving target. Rather than being permanently cemented in the cell’s blueprint, genetic changes introduced into short-lived RNA – since cells are constantly churning out new copies of RNA – could be halted or reversed. This potentially makes it a safer option than DNA editing.
Furthermore, RNA editing is simpler than DNA editing. CRISPR requires the delivery of bulky molecular machines made from bacterial proteins that cut genes, as well as an RNA molecule to direct the editing. RNA editing drugs, on the other hand, may not need to be delivered via lipid nanoparticles or viral vectors. For example, leading RNA editing company Wave Life Sciences uses short RNA-editing oligonucleotides that are chemically modified with N-acetylgalactosamine (GalNAc) to aid delivery. The advantage of this is that, unlike DNA editing systems, GalNAc-conjugated oligonucleotides can target the RNA to be taken up by cells.
However, according to Gregory Davis, a genome engineer at Sangamo Therapeutics, in an interview with Drug Discovery News, RNA editing does also have its disadvantages when compared to DNA editing. For example, he pointed to the fact that DNA editors need to act only on the two chromosomes in each cell. “That gives us the advantage of possibly lower dosing and more effective drug targeting. With RNA editing, you’ve got a lot more targets to take care of.”
Furthermore, Davis said that extending the lifespan of the RNA editor to reach all of those targets creates similar risks regarding lasting off-target effects: “DNA editing would be more permanent and heritable, but if you want this RNA editor to be effective for the patient, it’s going to be hanging around and being active. And if it has a wrong activity going along with that, you’re in the same situation.”
Plus, Davis added that the need for longevity in RNA editing also brings concerns about immunogenicity from nucleic acid-modifying enzymes.
But, considering RNA editing has only just reached the clinic, these are issues that could potentially be solved as more companies come up with innovative methods of RNA editing.
Wave Life Sciences initiates clinical trial of first-ever RNA editing candidate WVE-006
In September 2023, Wave Life Sciences submitted a clinical trial application for its RNA editing candidate, WVE-006. This was accepted, and dosing for that trial has now begun in the U.K., marking the first time an RNA editing candidate has reached the clinic.
WVE-006 is a synthetic RNA molecule that recruits a human enzyme called adenosine deaminase, or ADAR, to edit RNA. It is intended as a potential treatment for alpha-1 antitrypsin deficiency (AATD), an inherited genetic disorder that is commonly caused by a G-to-A point mutation (Z allele) in the SERPINA1 gene. This mutation leads to lung disease due to insufficient levels of circulating M-AAT protein.
Therefore, for patients with AATD, WVE-006 aims to correct the single base mutation in mRNA coded by the SERPINA1 Z allele, enabling the restoration and circulation of functional M-AAT protein in order to prevent liver damage and protect the lungs.
Wave now expects to deliver proof-of-mechanism data in individuals with AATD in 2024. It is also worth noting that the initiation of this trial saw Wave achieve its first milestone in its collaboration with GSK, resulting in a $20 million payment to the RNA editing company. As part of the collaboration, Wave is eligible to receive up to $505 million in additional development, launch, and sales-related milestone payments, as well as tiered royalties on net sales.
Ascidian Therapeutics receives FDA green light for first-ever RNA editing clinical trial in the US
More recently, in another milestone achievement for RNA editing, Ascidian Therapeutics – a biotech company based in Boston – received the go-ahead from the U.S. Food and Drug Administration (FDA) to begin the first-ever RNA editing clinical trial based in the U.S. And, while most companies developing RNA editing therapies, like Wave, recruit ADAR to edit DNA, Ascidian’s trial will be the first to test ‘exon editing’ in patients.
Ascidian gets both its name and technology from sea squirts, which are ocean creatures and primordial ancestors of vertebrates. To grow from larvae to adults, ascidians essentially shuffle small bits of RNA code known as exons. Inspired by this example, Ascidian uses a synthetic RNA molecule to intervene in the splicing process and persuade the cell to swap out a bunch of error-ridden exons for a corrected copy. Ascidian president and interim chief executive officer (CEO), Michael Ehlers, told Endpoints in a recent report that, by replacing the first 22 of 50 exons in the ABCA4 gene, the company believes it can treat roughly 60% to 70% of patients.
Ascidian’s candidate is called ACDN-01, and is the only clinical-stage therapeutic targeting the genetic cause of Stargardt disease – a rare genetic eye disease that happens when fatty material builds up on the macula, causing vision loss. More than 1,000 mutations across the ABCA4 gene have been found to cause Stargardt disease. However, diseases caused by ABCA4 loss of function cannot be addressed by standard gene replacement, given the large size of the gene, or by base editing, due to the high mutational variance of the affected gene. This is why RNA editing could be the best hope for correcting the genetic mutations responsible for these types of diseases.
Ascidian says it expects to initiate enrollment in the clinical study of ACDN-01 in Stargardt disease, as well as other ABCA4 retinopathies, in the first half of 2024. The FDA has also granted fast track designation for ACDN-01.
A promising future for RNA editing
All in all, although still in the early stages of clinical testing, it seems as though RNA editing could be a very promising technique to treat a number of diseases.
The second half of last year saw a sudden rise in the number of companies in the space. In August, San Francisco–based Amber Bio launched with an oversubscribed $26 million seed financing round. Then, AIRNA emerged from stealth with a $30 million initial financing. Plus, the RNA editing company Korro Bio and regenerative medicine company Frequency Therapeutics announced that they have entered into a definitive merger agreement to combine the two companies, with a focus on advancing Korro’s RNA editing programs.
Given it has a more favorable safety profile than DNA editing, as well as being simpler to deliver, it is easy to see why more and more companies are beginning to see the attraction of RNA editing. Now, we just have to wait and see how the new technology performs in the clinic, as we can expect to hear more about the progress of Wave’s and Ascidian’s trials later this year.
New technologies related to RNA:
- Cell-Selective Gene Editing – University of South Florida
- Site-directed RNA Editing by Engineered Human ADAR2 – Puerto Rico Science, Technology & Research Trust
- HyEdit – A Tool for Precision Genome Editing – EMBLEM Technology Transfer GMBH