Blog | 4/19/2024

Recruiting the Messenger RNA: The Future Role of RNA Editing in the Clinic

By Jeff Bessen, PhD, Vivek Mittal, PhD, and Ned Wydysh, PhD

The past 10 years may have been the decade of CRISPR DNA editing; however, RNA editing is now stepping into the spotlight. With splashy startup announcements, lucrative licensing deals, a surge in scientific publications, and several clinical trials underway by year’s end, RNA editing is undeniably having its moment. This exciting trend prompts us to consider the potential role of RNA editing-based therapies in future clinical practice. How do RNA editors compare to their DNA-based predecessors? Where will we see development of new therapies based on RNA editing? And how should sponsors of DNA-based gene therapies respond?
 

The Base-ics of RNA Editing

Similar to the variety of DNA editing technologies, there are also several different approaches being explored for RNA editing (Figure 1):

When compared to DNA-based gene therapies like AAV, lentivirus, and CRISPR gene editors, each type of RNA editor has its own set of advantages and disadvantages (Figure 2). Notably, RNA editors carry lower risks of genotoxicity, as they do not introduce permanent genomic edits. The programmable modification of mRNA also opens up intriguing possibilities for drugging targets that are challenging using traditional modalities. For instance, KRAS mutations are common in certain cancers, yet developing effective inhibitors has proven notoriously difficult. In theory, RNA editors could be directed against mutant KRAS mRNA to halt protein expression even before it occurs. Moreover, RNA editors could be suitable for scenarios where permanent gene silencing would be unwise – for example, treating post-operative pain by targeting specific ion channels in neurons.

Among RNA editors, the simplest variant is the ADAR recruiter, composed only of a synthetic RNA molecule. These recruiters offer a significant advantage over other gene editors: ease of in vivo delivery. Given that delivery remains a challenge in the field of gene therapy, this could represent a major breakthrough. Although ADAR recruiters have limitations, such as relying on endogenous ADARs which have limited RNA-editing capabilities and which play other biological roles in the cell, their potential appears high.              

The more complex RNA editors offer their own advantages, particularly the potential to edit large stretches of mRNA at once. This difference becomes most evident when comparing the Stargardt disease program of Ascidian Therapeutics versus a hypothetical CRISPR-based program. Stargardt disease can be caused by hundreds of mutations in the ABCA4 gene, leading to vision loss in affected patients. While DNA correction of the most common mutation, G1961E, could address ~15% of Stargardt patients, Ascidian’s ACDN-01 exon editor takes a more comprehensive approach. By replacing the first 22 exons of the ABCA4 gene in their entirety, ACDN-01 may potentially treat up to 70% of Stargardt patients.
 

Impact in the Clinic

Seemingly everywhere one looks, there are signs of growing momentum for RNA editing:

• Startups focused on RNA editing have garnered significant interest from investors. Amber Bio is the most recent entrant, emerging from stealth mode with $26MM in funding this past August. Collectively, RNA editing companies have raised more than $2B in funding from venture capital, IPOs, and post-IPO equity.
• Big Pharma has taken notice, with GSK, Roche, and Lilly signing partnerships with RNA editing sponsors in the past 3 years. Roche’s partnership with Shape Therapeutics could be valued at $3B or more.
• We likely haven’t seen the last of the RNA writers. That’s because, in just the last 3 months, researchers from UC Berkeley, MIT, and Duke have posted pre-print publications on their RNA editing technologies.

Most significantly, RNA editors have entered the clinic. Wave (WVE-006) and Rznomics (RZ-001) have begun dosing patients in the UK/Australia and South Korea, respectively. Ascidian (ACDN-01) has received FDA clearance for its IND, and Korro Bio (KRRO-110) will submit its IND application in the coming months. The first interim clinical readouts won’t be far behind.

Thus far, RNA editing sponsors have chosen to focus on therapeutic areas that largely overlap with established gene therapy indications (Figure 3). This phenomenon aligns with our recent white paper, which highlights how novel gene editing platform companies initially validate their platforms in de-risked indications. As the initial RNA editing programs yield positive clinical data, we will gain better insights into the long-term strategies for these platforms.

In response to the rise of RNA editing, sponsors who have previously invested in DNA-based gene therapies are adjusting their strategies. Many are placing their own bets on RNA editing. As mentioned earlier, some Big Pharma companies are diversifying by forming partnerships with RNA editors. Additionally, gene editing companies like Beam (and likely others) are actively developing their own in-house RNA editing technologies.       
 

Exciting Developments to Come

While it remains uncertain how RNA editors will compare to DNA editors clinically, we anticipate they will compete in some disease areas, while each also serving a distinct therapeutic niche. RNA editors may excel at temporally inhibiting ‘undruggable’ targets or addressing disorders in tissues where DNA-based gene therapies face delivery challenges. On the other hand, DNA editing is likely to maintain dominance in treating fatal genetic conditions like SMA or DMD, as well as diseases such as Sickle-Cell Disease and β-Thalassemia, where companies like CRISPR Therapeutics and bluebird bio have a significant head start.

The most intriguing question lies in the arenas where DNA and RNA editors compete head-to-head: which approach will gain wider adoption? How much weight will patients and prescribers place on the lower genotoxic risk associated with RNA editors versus the one-time curative potential of gene therapy? Which technology will overcome the delivery challenges posed by targeting the heart, lungs, and kidneys? We eagerly await seeing the field unfold.

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Jeff Bessen is a senior team leader within the Health Advances Cell and Gene Therapy practice.

Ned Wydysh, PhD is a Vice President and co-leader of Health Advances’ Oncology and Cell and Gene Therapy Practices

Vivek Mittal, PhD is a Partner, Managing Director, and co-leader of Health Advances’ Oncology and Cell and Gene Therapy Practices