RNA Editing Advances: New Hope for Rare and Common Diseases

RNA editing, a burgeoning field in genetic medicine, has made significant strides in recent years, offering potential treatments for both rare and common diseases. With the first human trial results emerging and multiple clinical studies underway, the pharmaceutical industry is witnessing a surge in RNA editing technologies that promise safer and more flexible alternatives to DNA editing.

Clinical Milestones and Therapeutic Potential

Wave Life Sciences has marked a pivotal moment in RNA editing by announcing the first-ever results from this mechanism in humans. The company's candidate, WVE-006, demonstrated promising outcomes in treating alpha-1 antitrypsin deficiency (AATD), a genetic condition affecting the lungs and liver. A single dose of WVE-006 led to increased levels of AAT in the blood, with the lowest dose achieving nearly therapeutic levels of editing.

Meanwhile, Ascidian Therapeutics has made history with ACDN-01, the first RNA exon editor to enter clinical development. Approved by the FDA for an investigational new drug application in January 2024, ACDN-01 targets Stargardt disease, an inherited retinal disorder. This candidate aims to correct the fundamental cause of the disease by replacing 22 exons of the ABCA4 gene, potentially addressing hundreds of mutations across the patient population.

Expanding Applications and Delivery Breakthroughs

RNA editing's potential extends beyond rare diseases. Paul Bolno, President and CEO of Wave Life Sciences, highlighted its application in upregulation, which could treat diseases by increasing protein expression. One promising area is cholesterol lowering, where RNA editing could increase the density of LDL receptors on cell surfaces.

Delivery remains a significant challenge in the field. However, progress is being made in extra-hepatic applications, opening up possibilities for treating conditions such as cystic fibrosis and MECP2 duplication syndrome. This advancement could potentially benefit over 10 million patients across various diseases.

To address delivery challenges, collaborations are forming within the industry. Ascidian Therapeutics secured a deal worth up to $1.8 billion with Roche in June 2024 to discover RNA exon editing candidates for neurological diseases. This partnership aims to leverage Roche's expertise in delivering therapeutics across the blood-brain barrier and to other tissues of interest.

Technological Advancements and Future Directions

The evolution of RNA editing technologies has been rapid over the past decade. Key developments include the discovery of ADAR (adenosine deaminase acting on RNA) for single-base swaps, the REPAIR technology fusing CRISPR-Cas13 with ADAR, and the RESCUE tool enabling cytidine to uridine conversion.

Despite these advancements, challenges remain. Current editing efficiency is low, with only about 2% of target molecules being successfully edited. Researchers are working to improve this, with companies like Ascidian reporting higher levels of RNA editing efficiency.

As the field progresses, attention is turning to expanding editing capabilities. Silvi Rouskin, an assistant professor of microbiology at Harvard Medical School, notes that once it becomes possible to edit any base to another, RNA editing could potentially address any well-understood disease that requires genetic correction.

While off-target effects are a consideration, experts believe they are less critical at current efficiency levels. However, as editing capabilities improve, this may become a more significant concern requiring further research and mitigation strategies.