RNA editing is emerging as a promising and potentially safer alternative to therapies that modify an individual’s DNA. In December 2023, patients were treated in the first clinical trial for an RNA-editing therapy. This marked a significant milestone and could set the stage for further advancements. RNA editing aims to temporarily alter protein structures or quantities by modifying the molecules that carry instructions for protein production, not the original DNA blueprint.
Temporary and Targeted: The Advantages of RNA Editing
Unlike DNA editing, which can cause permanent changes and unintended effects, RNA editing results in temporary modifications. This makes the approach potentially safer, as any genetic changes can be stopped or reversed because cells continually produce new RNA copies.
RNA editing also simplifies the editing process. While CRISPR technology uses complex molecular machinery, RNA editing therapies often use more straightforward delivery methods. For instance, the company Wave Life Sciences employs chemically modified short RNA-editing oligonucleotides to aid delivery, targeting RNA for cellular uptake without the need for viral vectors or lipid nanoparticles.
Challenges and Considerations
Despite the greater safety risks of DNA editing, there are some advantages. Gregory Davis, a genetic engineer at Sangamo Therapeutics, highlights that DNA editors only need to target two chromosomes per 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.”
In contrast, RNA editing must address numerous targets within the cell, increasing the complexity and potential for unintended consequences. “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,” Davis explained.
Immunogenicity is another concern, as nucleic acid-modifying enzymes used in RNA editing could provoke immune responses. These challenges need to be addressed as RNA editing moves forward, but the potential for innovative solutions remains high.
Milestone Trials: Wave Life Sciences and Ascidian Therapeutics
Wave Life Sciences is conducting the first clinical trial of an RNA editing candidate. The Phase I trial in the United Kingdom is evaluating WVE-006, a synthetic RNA molecule that employs the human enzyme adenosine deaminase (ADAR) to target a mutation in the SERPINA1 gene responsible for alpha-1 antitrypsin deficiency (AATD). The therapy aims to correct this mutation and restore levels of the protein M-AAT to prevent liver damage and protect the lungs. The company anticipates that the trial will provide proof-of-mechanism data in 2024.
Ascidian Therapeutics also reached a significant milestone when it received FDA approval for the first RNA exon-editing clinical trial. Ascidian’s approach, inspired by sea squirts, uses synthetic RNA molecules to correct errors in RNA splicing. The candidate, ACDN-01, is the only clinical-stage therapeutic to target Stargardt disease, a rare genetic eye disease. The trial is set to begin in the first half of 2024 and aims to address the genetic cause of this disease by correcting mutations in the ABCA4 gene.
The Future of RNA Editing
RNA editing holds great promise for treating a range of diseases. The second half of 2023 saw a surge in interest and investment in RNA editing companies. Amber Bio raised $26 million in seed financing, AIRNA received $30 million in initial financing and Korro Bio announced a merger with Frequency Therapeutics to advance RNA editing programs.
RNA editing is attracting increasing attention partly because of its advantages over DNA editing. The current and upcoming clinical trials with candidates from Wave Life Sciences and Ascidian Therapeutics will be key factors in demonstrating the efficacy and safety of this new technology. As the field progresses, RNA editing could become a vital tool in genetic medicine, offering new hope for patients with genetic diseases.
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