RNA therapeutics: a review of the future of medicine | eBlog

Traditional drug discovery has focused on using small molecules that act on proteins to treat a disease. However, only a small portion of the genome codes for proteins and of those proteins it is estimated that less than 25% are feasible targets for small molecule activity1,2. Due to the limitations of small molecules, interest in RNA therapeutics has increased significantly over the past decades as they allow for the entire transcriptome to be targeted by using sequence complementarity or by providing the template to generate therapeutic proteins. In this eBlog we review several classes of RNA therapeutics and the history of their development.

Antisense oligonucleotides (ASOs): regulators of splicing, translation, and stability

ASOs are short, single-stranded oligonucleotides that use sequence complementarity to specifically bind to their target transcripts3,4. They can act either through recruiting RNase H to degrade the target RNA or by sterically blocking the activity of another factor such as RNA-binding proteins or miRNAs.

ASOs were the first RNA therapeutic to be developed when, in 1978, it was used to inhibit Rous sarcoma virus4. There was then a 20-year gap between this initial development and regulatory approval with fomivirsen, an ASO to treat cytomegalovirus retinitis, receiving approval in 1998 (although it was later withdrawn)5. Eight ASOs are approved and on the market, and there are over 40 preclinical or clinical trials related to ASOs3,6,7. The majority of ASOs in clinical trials are focused on genetic diseases, like the approved nusinersen which blocks the binding of proteins to SMN2 to regulate splicing8.  

Approved ASOs act by degrading RNA or changing splicing to include or exclude exons, although there are other potential uses for ASOs including regulating translation and miRNA binding9,10.

NameYear ApprovedManufacturerCondition or Disease
Nusinersen2016Ionis/BiogenSpinal muscular atrophy
Eteplirsen2016SareptaDuchenne muscular dystrophy
Inotersen2018Ionis/AkceaTransthyretin-mediated amyloidosis
Golodirsen2019SareptaDuchenne muscular dystrophy
 Viltolarsen2020NS PharmaDuchenne muscular dystrophy
Casimersen2021SareptaDuchenne muscular dystrophy
Tofersen2023Ionis/BiogenAmyotrophic lateral sclerosis
Eplontersen2023Ionis/Astra ZenecaTransthyretin-mediated amyloidosis
Table 1: List of FDA-approved ASO drugs. ASOs that have been approved but removed from the market are not listed6,14. Milasen, not included in the table, is an ASO approved in 2018 for the personalized treatment of Batten Disease.

Aptamers: regulators protein activity

Aptamers are single-stranded oligonucleotides like ASOs, but instead of binding to other RNAs they form three-dimensional structures that can inhibit protein activity4. Aptamers were first described in 1990 and Pegaptanib, targeting VEGF, was approved in 2004 (although later discontinued). Despite their potential to regulate proteins with a high degree of specificity, there is only one apatamer on the market and there are only a few clinical trials in progress14.

NameYear ApprovedManufacturerCondition or Disease
Avacincaptad pegol2023Iveric BioMacular degeneration
Table 2: List of FDA-approved apatamer drugs. Aptamers that have been approved but removed from the market are not listed14.

siRNAs: regulators of gene expression

siRNAs are short double-stranded oligonucleotides that lead to the activation of RNA interference (RNAi) and RNA degradation. During the RNAi process, the siRNA is loaded into Argonaute 2 (AGO2), part of the RISC complex. The passenger strand is degraded, leaving behind the single-stranded guide, which binds with perfect sequence complementarity to the target mRNA leading to the degradation of the mRNA via AGO24.

RNAi was first described in 1998 when it was found that double-stranded RNA leads to transcript degradation, and although later academic research showed that siRNAs could activate RNAi, it took 20 years for the first siRNA drug (patisiran) to be approved in 20182,11. Since the approval of patisiran, an siRNA drug has been approved by the FDA every year and there are over 50 clinical trials related to siRNAs6. These trials include treatment of genetic diseases, non-genetic physiological disorders, and cancers6.

siRNAs are a powerful therapeutic for regulating gene expression although several challenges remain including off-target effects arising from partial binding, targeting to the proper tissue, and endosomal escape when LNPs are used as the delivery mechanism13.

NameYear ApprovedManufacturerCondition or Disease
Patisiran2018AlnylamTransthyretin-mediated amyloidosis
Givosiran2019AlnylamAcute hepatic porphyria
Lumasiran2020AlnylamPrimary hyperoxaluria
Inclisiran2021Novartis/AlnylamHeterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease
Vutrisiran2022AlnylamTransthyretin-mediated amyloidosis
Nedosiran2023DicernaPrimary hyperoxaluria
Table 3: List of FDA-approved siRNA drugs. siRNAs that have been approved but removed from the market are not listed6,14.

mRNAs: providing the code for proteins

mRNA therapeutics introduce mRNA into the cell, leading to the production of a therapeutic protein. One of the main strengths of mRNA therapeutics is that, unlike siRNAs and ASOs, the goal is to increase the level of a protein rather than decrease it. As such, the therapeutic applications of mRNA are extensive including: infectious disease vaccines, personalized medicines for cancers, and protein replacement13. Also under the broad umbrella of mRNA-based therapeutics are monoclonal antibodies and mRNA-based methods for gene editing such as CRISPR13.

mRNA was first discovered in 1961, T7 for in vitro transcription was commercialized in 1985, and clinical trials for mRNA were started in 2002, although it wasn’t until the SARS-CoV-2 pandemic that mRNAs first received regulatory approval13. Since then, mRNAs have rapidly become a preferred RNA therapeutic with over 100 mRNA clinical trials as of 20226. Many of the clinical trials are focused on infectious disease after the success of the SARS-CoV-2 vaccines, but there are also trials related to treating cancer and genetic diseases6. For example, Moderna has recently seen success in clinical trials for a dual mRNA therapy to treat propionic acidemia16.

Although mRNA can act as a potent therapeutic, there are several challenges that remain for successful drug development. They include proper codon optimization to ensure efficient translation, effective design of the UTRs and coding sequence to prevent endogenous regulation, and enhancing endosomal escape to increase the amount of RNA entering the target cell.

NameYear ApprovedManufacturerCondition or Disease
Table 4: List of FDA-approved mRNA vaccines.

RNA therapeutics are the future of medicine, Eclipsebio helps our partners achieve success

Although the history of RNA therapeutics has shown extended timelines between the discovery of a potential therapeutic and its approval for the clinic, nucleic acid therapies are rapidly becoming the preferred treatment modality. From a new siRNA drug being released every year, to tailored mRNA therapeutics, RNA-based drugs are the future of medicine. At Eclipsebio we are looking forward to continuing to help our partners characterize and optimize their RNA therapeutics. If you are interested in learning how our integrative technologies can be used to improve therapeutic development, contact us today.

  1. Bojadzic and Buchwald
  2. Ghadermarzi et al.
  3. Damase et al.
  4. Zhu et al.
  5. Bradley
  6. Curreri et al.
  7. Sasso et al.
  8. Marasco et al.
  9. Collotta et al.
  10. Lima et al.
  11. Hu et al.
  12. Zaidi et al.
  13. Qin et al.
  14. Al Shaer et al.
  15. Al Musaimi et al.
  16. Koeberl et al.

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