Opinion: Interest in RNA Editing Accelerates as Therapies Approach the Clinic

Based on the significant progress made over the last few decades with RNA therapeutics, RNA editing is widely considered the next generation of promising medicines in this field.

RNA therapies have made significant progress over the last few years, with an increasing number of FDA approvals beginning in 1998 with Vitravene for CMV retinitis, followed by Macugen for macular degeneration in 2004 and Spinraza for spinal muscular atrophy in 2016. There have also been multiple siRNA-based drugs, including Onpattro for polyneuropathy of hereditary transthyretin-mediated amyloidosis in 2018. And finally, in 2020, perhaps the most well-known products in the RNA space were introduced: the mRNA-based COVID-19 vaccines.

All of these demonstrate the strength of RNA therapies and their potential impact on diseases with high unmet need.

RNA therapeutics are indeed elegant approaches to altering RNA and thus protein expression, opening the potential to target a broad array of diseases. The field has seen a renewed and increased interest as reversible changes offer flexibility and RNA approaches introduce therapeutic opportunities that were not accessible before.

RNA editing technology was first known and recognized as an interesting approach to treating genetic conditions and reversing disease-causing mutations at the RNA level. RNA editing is a naturally occurring and highly active process that uses the body’s existing capabilities to perform nucleotide changes. Since 2014, when ProQR Therapeutics invented the technique of using oligonucleotides recruiting endogenous adenosine deaminase action on RNA, known as ADAR-mediated editing, the field has rapidly progressed.

This growth can be attributed to the rapid progression of knowledge about the technology. Alpha-1 antitrypsin deficiency (AATD) is the first indication that many RNA editing companies have decided to pursue, as it provides the opportunity to address liver and lung symptoms of the disease. Clinical trials for AATD run by both Wave Life Sciences and Korro Bio are planned to begin this year and next.

Genetic and Common Disorders

There is great excitement in the field about using learnings from decades of oligonucleotide-based drug development, natural RNA editing, and knowledge of biological pathways to make RNA editing technology a compelling approach to target various pathophysiological processes. This offers, for example, the possibility not only of reducing or restoring protein expression but also of modulating protein activity involved in diseases. This application of RNA editing offers the potential to impact both genetic disorders and common conditions, such as metabolic and cardiovascular diseases.

ProQR’s approach differentiates RNA editing, as it provides the opportunity to target conditions that have thus far not been treatable with other technologies. Indeed, RNA editing offers the possibility of introducing protective variants, informed by human genetics, that could address or prevent diseases including certain cholestatic or cardiovascular conditions. For example, it has been reported in the literature that an Old Order Amish-enriched variant in a functional B4GALT1 was associated with lower serum LDL-C and lower plasma fibrinogen. This protective variant can be introduced via ADAR RNA editing technology, which has the potential to simultaneously address the two cardiovascular risk factors.

Delivery is an important aspect of oligonucleotide base therapeutics. RNA therapies, including RNA editing, have again made great progress and generally use conjugation or lipid nanoparticle approaches. As an example, Alnylam made tremendous progress in its siRNA-based treatments for amyloidosis, with Onpattro in 2018 offering an intravenous treatment once every three weeks. Only four years later, Amvuttra arrived on the market for the same condition but with a subcutaneous 3-month dosing approach.

For now, the majority of RNA editing programs are focused on targeting the liver where delivery is relatively de-risked, although progress is also being made in exploring new frontiers such as the central nervous system, as evidenced by the partnerships between Roche and Shape Therapeutics and ProQR and Eli Lilly.

In summary, the RNA editing space is making impressive progress. The recent approvals and clinical results demonstrating the potential of RNA therapy to target a broad array of organs are extremely encouraging for RNA editing. Near term, we expect to see further development of the technology, more programs advancing to clinical development, expansion of therapeutic areas addressed, and ultimately, we are hopeful that the next few years will bring considerable progress for patients in need.

Gerard Platenburg is a cofounder of ProQR and has served as the company’s chief scientific officer since 2022. Gerard has an extensive background in RNA modulation and orphan drug discovery and development and currently leads ProQR’s Innovation unit.

PackGene is a CRO & CDMO technology company that specializes in packaging recombinant adeno-associated virus (rAAV) vectors. Since its establishment in 2014, PackGene has been a leader in the AAV vector CRO service field, providing tens of thousands of custom batches of AAV samples to customers in over 20 countries. PackGene offers a one-stop CMC solution for the early development, pre-clinical development, clinical trials, and drug approval of rAAV vector drugs for cell and gene therapy (CGT) companies that is fast, cost-effective, high-quality, and scalable. Additionally, the company provides compliant services for the GMP-scale production of AAVs and plasmids for pharmaceutical companies, utilizing five technology platforms, including the π-Alpha 293 cell AAV high-yield platform and the π-Omega plasmid high-yield platform. PackGene's mission is to make gene therapy affordable and accelerate the launch of innovative gene drugs. The company aims to simplify the challenging aspects of gene therapy development and industrialization processes and provide stable, efficient, and economical rAAV Fast Services to accelerate gene and cell therapy development efforts from discovery phase to commercialization.

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