RNA Therapeutics: Four Key Modalities Reshaping Medicine

1 Listicle RNA therapeutics are a versatile drug class made from ribonucleic acid that have rapidly gained momentum over the last decade, redefining how diseases can be treated. Conventional drug modalities, such as small molecules, typically target disease symptoms. However, RNA therapeutics go to the root cause or pathway of the disease. This means they can be designed for targets previously considered “undruggable”.1 These therapeutics were slow to take off until 2016, when Spinraza was approved to treat spinal muscular atrophy. Fast forward to the start of 2025, and 34 RNA therapies have been approved globally for clinical use, with many more in the development pipeline.2 RNA therapeutics have an advantage over small molecules and antibodies, in that they can be developed quickly by using existing design and delivery technologies.3 They are chemically synthesized, which allows for rapid production4 and they have the benefits of a vast selection of disease targets, robust and long-lasting efficacy and a high development success rate.5 This modality has now been used to treat conditions such as cancer, cardiometabolic and CNS disorders, rare genetic diseases and used as vaccines.2 It has also been used for personalized medicine.6 There are challenges for this drug type, largely with delivery and uptake into target cells. In addition, these therapeutics are unstable and can be degraded by nucleases.7 In this listicle, we explore the key types of RNA therapeutics, milestones in their development history, success stories and challenges. mRNA vaccines mRNA vaccines are well known for their successful application against COVID-19 in 2020. However, they first appeared in 1995 for a cancer treatment in mice. By 2013, the first clinical trial in humans began using an mRNA vaccine for infectious disease.8,9 Then in 2020, the mRNA-based COVID-19 vaccines were rapidly developed, by inserting new mRNA sequences into existing mRNA design and delivery methods for fast clinical testing. Emergency use approvals came in 2020, with full approvals in 2021.8 After a flurry of activity with a series of vaccines all targeting COVID-19, 2024 saw the approval of mRESVIA for respiratory syncytial virus (RSV).10 This is the first commercially available mRNA vaccine to target a different infectious disease, highlighting the potential for more mRNA-based preventive treatments. In fact, for any pathogen with a known protein target, it should be possible to produce an mRNA vaccine.4 The mechanism for these vaccines involves encoding antigens in mRNA and delivering them into the host cell cytoplasm via a non-viral delivery route, where they are then expressed and stimulate a specific immune response.4 RNA Therapeutics: Four Key Modalities Reshaping Medicine Katie Minns, PhD RNA THERAPEUTICS: FOUR KEY MODALITIES RESHAPING MEDICINE 2 Listicle Despite the rapid success of this vaccine platform, there are challenges. mRNA is unstable and susceptible to degradation, so the vaccines must be enclosed in a delivery system. Lipid nanoparticles (LNPs) are used to facilitate uptake into cells through endocytosis, while also allowing escape once inside the cell for translation in the cytoplasm. 7 Cold storage is another challenge for these vaccines, with some needing to be kept at temperatures below -60 °C.3 This proved to be a challenge for vaccinating care home residents during the COVID-19 pandemic, forcing early batches of available vaccine to be diverted to alternative high-priority groups.11 While the vaccine must be able to generate a strong immune response, excessive immunogenicity is a risk for adverse reactions. Modifications to the mRNA structural elements, such as chemically altering nucleotides and adding poly(A) tails, can minimize these effects and improve stability.12 Antisense oligonucleotides Antisense oligonucleotides (ASOs) are short, single-stranded oligos, approximately 12–24 bases long.13 They target endogenous RNA, including noncoding RNA and mRNA3 and affect the expression of specific target RNAs by two mechanisms. Either triggering RNase H1 or ribozymes to cleave target mRNA, or by regulating gene expression. This can occur in a number of ways, including altering splice patterns to skip or include particular exons, inhibiting or activating translation, via mRNA decay, or by blocking microRNAs from binding to target mRNA.13 Fomivirsen was the first RNA therapeutic approved for use in 1998 for the treatment of retinitis caused by cytomegalovirus.14 Since then, 13 ASOs have been approved for use, mostly targeting genetic diseases, with 4 approved for treating Duchenne muscular dystrophy (DMD) — an X-linked genetic disorder mostly affecting young boys.3 Other ASO success stories include the 2024 approval of imetelstat for myelodysplastic syndrome,15 representing a novel approach to treating this type of cancer.16 This class of RNA therapeutic also represents the first example of a drug being made for a single patient, showing the true potential of personalized medicine.6 One of the main challenges of ASO therapeutics is enabling them to reach their target sites. Modifications of the phosphate backbone, ribose ring and bases are often used to overcome this, improving nuclease resistance and delivery.3 Conjugating the therapeutic oligo to a ligand or using nanoparticles can also aid delivery.13 Small interfering RNA Small interfering RNAs (siRNAs) are short double-stranded RNAs, around 21–25 nucleotides long, that are used in a process called RNA interference (RNAi).17 After uptake into the cell, siRNAs are cut by an endoribonuclease called Dicer, then loaded onto a protein complex including Argonaute. The strands of the RNA duplex are separated and the “passenger” strand is ejected. The “guide” strand, that is complementary to the mRNA sequence of interest, remains bound to Argonaute and together become the RNA-induced silencing complex (RISC). This directs silencing by cleaving the target sequence or repressing translation, resulting in decreased production of specific proteins.17 The first siRNA therapeutic approved for clinical use was patisiran in 2018 for the treatment of hereditary transthyretin-mediated amyloidosis – a rare, progressive and often fatal disease. As with other types of RNA THERAPEUTICS: FOUR KEY MODALITIES RESHAPING MEDICINE 3 Listicle RNA therapeutic, delivery is a major challenge for siRNA. Patisiran mitigates this by utilizing a LNP delivery mechanism.18 However, LNPs have their own challenges, including that they trigger an innate immune response which can cause adverse effects.19 The five siRNAs approved since patisiran all use conjugation with N-acetylgalactsamine (GalNAc). GalNAc binds the asialoglycoprotein receptor, which is highly expressed on the surface of hepatocytes, facilitating efficient uptake of siRNAs bound to it.20,21 Other challenges of siRNAs include stability and protection from nucleases. Modifications, such as phosphorothioate and methylene insertion, can be used to protect the backbone of the oligonucleotide.22 One benefit of the RNAi technique is the abundance of targets, offering flexibility to drug developers and clinicians. For example, two siRNA drugs, lumasiran and nedosiran, are both designed to treat primary hyperoxaluria – characterized by the excessive synthesis of oxalate in the liver, leading to kidney disease – but they differ in their specific targets and mechanisms of action.21,23 RNA aptamers RNA aptamers are single-stranded oligonucleotides that fold into well-defined structures that specifically bind to proteins and other targets.1,13 They can be used as antagonists to block interactions between proteins, or receptors and ligands. Or they can also function as delivery agents when conjugated to drugs.13 Aptamers function in a similar manner to antibodies but have several advantages when compared to them. Their flexible nature means they can fold into or around a wide range of targets, they have high thermal stability, and because they are chemically synthesized, they can have rapid, scalable production.24 The first aptamer drug to be approved was Macugen, in 2004, for treating wet age-related macular degeneration (wet AMD) – a cause of blindness. This was discontinued in 2020,3 although in 2023 a new RNA aptamer drug, Izervay, was approved to treat geographic atrophy secondary to AMD.25 This remains the only RNA aptamer commercially available, although there are others in development.26 Unlike the other RNA therapeutic types, delivery is not such a challenge due to aptamer targets typically being extracellular. However, they are unstable and at risk of clearance. Base modifications and conjugation with biocompatible polymers, such as polyethylene glycol (PEG) can help to mitigate these problems.3 Future outlook As the field advances, RNA therapeutics continue to expand into new applications and disease areas, offering hope to those with rare diseases or previously untreatable conditions. As new solutions are found to address the challenges with delivery and stability, the potential of these platforms will be unleashed further. Related technologies, including CRISPR gene editing and RNA editing, are also expanding the possibilities for precise genetic interventions. These approaches complement RNA therapeutics, potentially offering even more targeted and long-lasting treatments. However, the permanent nature of gene editing carries additional risk, meaning that RNA therapeutics are a safer option while offering many of the same benefits. 3 Sponsored by RNA THERAPEUTICS: FOUR KEY MODALITIES RESHAPING MEDICINE 4 Listicle References 1. 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