RNA Editing Is on the Rise – Can It Overcome the Limitations of CRISPR Gene Editing?

Recently, RNA editing has made major advances as a potentially safer alternative to gene editing for treating various genetic diseases. In December 2023, patients were dosed in the first clinical trial of an RNA-editing candidate—a milestone that could see the field take off in the coming months.

Why Do We Edit Genes or Gene Products?

Editing genes (DNA) or their product, RNA, has the potential to treat genetic disorders by correcting faulty genes. RNA editing can temporarily alter gene expression without permanently changing DNA, potentially preventing unwanted permanent side effects. These technologies may offer new approaches, particularly for rare genetic diseases that are difficult to treat. Gene and RNA editing also target underlying causes rather than symptoms, potentially providing more effective and lasting solutions.

What Exactly Is RNA Editing, and How Does It Differ From DNA Editing?

Both DNA and RNA editing aim to change the structure or quantity of a protein. Unlike DNA editing, RNA editing allows scientists to alter the molecules carrying instructions for protein production without changing the original DNA code.

A major advantage of RNA editing is its temporary effects. DNA editing can cause 'off-target effects' when errors occur. For example, a study published in Cell showed that a mutation-correcting CRISPR-Cas9 system cut and rejoined DNA strands in the wrong place or failed to repair them more than half the time, causing chromosome loss. RNA, by contrast, is a less problematic target. Rather than becoming permanently fixed in cellular DNA, changes introduced into short-lived RNA can be stopped or reversed because cells continually produce fresh RNA copies. This may make it safer than DNA editing.

RNA editing is also simpler than DNA editing. CRISPR requires delivery of bulky molecular machinery consisting of bacterial proteins that cut genes, as well as an RNA molecule to guide the edit. RNA-editing drugs, by contrast, may not require lipid nanoparticles or viral vectors for delivery to tissues. Wave Life Sciences, a leading RNA-editing company, uses short RNA-editing oligonucleotides chemically modified with N-acetylgalactosamine (GalNAc) to facilitate delivery. The advantage is that, unlike DNA-editing systems, GalNAc-linked oligonucleotides can target RNA to be taken up by cells.

However, Gregory Davis, a genome engineer at Sangamo Therapeutics, explained in an interview with Drug Discovery News that DNA editing alters chromosomes, the foundation of cellular genetic material. Since each cell has only two copies, an edit can generally be completed once. RNA editing targets the RNA molecules copied from DNA and used to make proteins, of which many copies may exist in a cell. Because many more molecules must be targeted, RNA editing may be more difficult and complex than DNA editing. Davis says: "CRISPR probably gives us the advantage of lower dosing and more effective drug targeting. With RNA editing, there are many more targets to address."

Davis notes that RNA editors remaining active for a long time may risk unwanted, permanent side effects similar to those of DNA editing. DNA editing makes permanent genetic changes that can pass to future generations. Long-lasting RNA editors can also produce unwanted effects if they act in nontargeted locations. In other words, persistent RNA-editing activity in the wrong place can cause problems resembling off-target effects in DNA editing.

According to Davis, enzymes used for RNA editing that need to remain in the body for a long time could affect the immune system. Enzymes modifying nucleic acids may be recognized as foreign and trigger unwanted immune responses.

Nevertheless, RNA editing has only recently entered human clinical studies. These problems could potentially be addressed as more companies develop innovative approaches.

Wave Life Sciences Launches a Clinical Trial of Its First RNA-Editing Candidate, WVE-006

In September 2023, Wave Life Sciences submitted a clinical trial application for its RNA-editing candidate WVE-006. It was accepted, and a dose-finding trial has now begun in England, marking the first time an RNA-editing candidate has reached the clinic.

WVE-006 is a synthetic RNA molecule that uses 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 disorder usually caused by a G-to-A point mutation (the Z allele) in the SERPINA1 gene. This mutation causes lung disease because of insufficient circulating M-AAT protein.

For patients with AATD, WVE-006 therefore aims to correct the single-base mutation in mRNA encoded by the SERPINA1 Z allele, restoring functional M-AAT protein and its circulation to prevent liver damage and protect the lungs.

Wave aims to share data in 2024 showing the activity and mechanism of its RNA-editing treatment in people with AATD. Starting this trial met the first milestone in its collaboration with GSK, triggering a payment of 20 million dollars to the RNA-editing company. Under the agreement, Wave is eligible for up to 505 million dollars in additional development, launch, and sales milestones, plus tiered royalties on net sales.

Ascidian Therapeutics Receives FDA Clearance for the First RNA-Editing Clinical Trial in the United States

In another recent milestone for RNA editing, Boston-based Ascidian Therapeutics received United States Food and Drug Administration (FDA) clearance to begin the first RNA-editing clinical trial in the United States. Whereas Wave, like most companies developing RNA-editing therapies, uses ADAR to edit DNA, Ascidian's trial will be the first to test "exon  editing" in patients.

Ascidian takes both its name and technology from sea sponges, marine organisms described as primitive ancestors of vertebrates. To grow from larvae into adults, ascidians essentially rearrange small pieces of RNA code called exons. Inspired by this example, Ascidian intervenes in splicing with a synthetic RNA molecule that persuades the cell to replace a cluster of faulty exons with a corrected copy. In a recent Endpoints report, CEO Michael Ehlers said that replacing the first 22 of the ABCA4 gene's 50 exons could allow the company to treat approximately 60% to 70% of patients.

Ascidian's drug candidate ACDN-01 is the only clinical-stage treatment targeting the genetic causes of Stargardt disease. This rare genetic disorder causes vision loss through fat accumulation in the macula and is associated with more than 1,000 mutations in ABCA4. Because of ABCA4's large size and mutational diversity, standard gene replacement or base-editing approaches are insufficient for treating the disease. RNA editing therefore has significant potential to correct mutations in disorders caused by loss of ABCA4 function.

The Promising Future of RNA Editing

The RNA-editing sector grew substantially over the past year, with many new companies entering the field and increasing investment. San Francisco-based Amber Bio raised 26 million dollars in financing, attracting strong investor interest. AIRNA then entered with 30 million dollars in seed funding. RNA-editing company Korro Bio and regenerative medicine company Frequency Therapeutics also agreed to merge, focusing on developing Korro's RNA-editing programs. These developments underline confidence in the technology's future and its potential.

RNA editing is attracting many companies because of its potentially safer profile and simpler implementation compared with DNA editing. Its clinical results are eagerly awaited, with important data expected this year from trials run by Wave and Ascidian.