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Top 7 Most Exciting RNA Modalities Being Developed Today

  • Writer: Michael Nguyen
    Michael Nguyen
  • 2 days ago
  • 4 min read

RNA therapeutics are transforming the future of healthcare with targeted gene therapies.


What are RNA therapeutics? 


RNA molecules, transcribed from DNA, convey genetic information to machinery responsible for protein synthesis. RNAs play many crucial roles in cells. They can turn genes on and off, help chemical reactions happen, cut and join other RNAs, and even help build proteins by carrying and connecting amino acids. By harnessing the abilities of RNA, scientists can combat diseases more effectively and efficiently than previous options9.


What are the advantages of RNA therapeutics? 


  • Cost effective - compared to recombinant proteins or small molecules, RNA therapeutics are relatively simple to manufacture, making them more cost-effective2.

  • Personalized treatment - RNA can be modified to custom sequences to correct specific issues2

  • Targets pathways that were previously undruggable - Some illnesses are caused by faulty genes or proteins that other medicines can’t reach. RNA therapeutics can intervene by blocking harmful proteins, correcting genetic instructions, or producing missing proteins, addressing challenges that earlier treatments could not overcome2. ​


Top 7 Most Exciting RNA Modalities being Developed Today


  1. Messenger RNA (mRNA) - mRNA is the intermediate between coding DNA and encoded proteins. mRNA copies the instructions from DNA and carries them to the cell’s protein making machinery, which uses the instructions to make the necessary proteins. Synthetic mRNA gives us a way to intentionally make the proteins needed to prevent, treat, or cure diseases4. (Average size: 1000-5000 nucleotides, so quite large)

    Fig. 1 - mRNA Therapeutic Workflow
    Fig. 1 - mRNA Therapeutic Workflow

  2. Guide RNA (gRNA/sgRNA) - Guide RNA, especially in the context of CRISPR-Cas9 gene editing, involves using synthetic RNA molecules to lead the Cas9 enzyme to specific DNA sequences for targeted gene editing6. Cas9 is an endonuclease that breaks double-stranded DNA, which allows the genome to be modified5 (30-100 nt). . 


  3. Antisense Oligonucleotides (ASOs) -  ASOs are synthetic, short, single-stranded RNA or DNA molecules that hybridize to target RNA through complementary base pairing. Once bound to target RNA, ASOs can block RNA translation3, induce RNA degradation1, and alter RNA splicing7. (15-25 nt).


  4. Small Interfering RNA (siRNA) - siRNA facilitates RNA interference (RNAi) by directing the RNA-induced silencing complex (RISC) to target mRNA molecules with complementary sequences, which leads to mRNA gene silencing through degradation into short fragments8. (19-25 nt)


  5. MicroRNA (miRNA) - miRNAs act as regulators of gene expression by binding to target mRNAs through partial sequence complementarity (base pairing between two strands isn't perfect), mostly within the 3’ untranslated region (UTR). This leads to mRNA degradation or translational repression. (18-25 nt)


  6. Circular RNA (circRNA) - circRNAs are covalently closed-loop RNA molecules that exhibit enhanced stability compared to linear RNAs, making them less susceptible to exonuclease degradation. This stability translates to prolonged protein expression, which is advantageous for therapeutic applications. CircRNAs can function as microRNA sponges, regulate transcription, and even encode proteins. (100-4000 nt)


  7. Self-amplifying RNA (saRNA) - saRNAs are engineered RNA molecules that retain the replication machinery of certain viruses but lack the components necessary for producing infectious particles. Once inside a cell, saRNAs can replicate themselves, leading to higher protein production from a smaller initial dose. This property is particularly beneficial for vaccine development and protein replacement therapies, as it can enhance efficacy while reducing the required dosage. ​(9000-12000 nt)


What's Challenging RNA Therapeutics Today?


1. Delivery Challenges


Delivering RNA molecules to target cells remains a significant hurdle. Naked RNA is prone to rapid degradation by nucleases and has difficulty crossing cell membranes. While lipid nanoparticles (LNPs) have improved delivery efficiency, issues like endosomal escape and tissue-specific targeting persist. ​


2. Stability and Degradation


RNA molecules are inherently unstable and susceptible to enzymatic degradation. Chemical modifications, such as incorporating modified nucleosides, can enhance stability but may also affect the molecule's functionality. ​


3. Immunogenicity


Exogenous RNA can trigger immune responses, leading to inflammation and reduced therapeutic efficacy. Strategies like nucleoside modifications aim to mitigate this, but balancing immunogenicity and therapeutic activity remains complex. ​


4. Manufacturing and Scalability


Producing RNA therapeutics at scale with consistent quality is challenging. Ensuring purity, avoiding contaminants, and maintaining batch-to-batch consistency are critical for clinical applications. ​


5. Target Specificity and Off-Target Effects


Achieving precise targeting to specific cells or tissues is essential to minimize off-target effects. Current delivery systems lack the specificity required for certain applications, leading to potential side effects. ​


As RNA therapeutics continue to evolve, they are reshaping the landscape of modern medicine. From synthetic mRNA vaccines to gene-editing tools like gRNA, these innovations offer promising solutions for treating genetic disorders, cancers, and previously untreatable diseases. With ongoing research and expanding clinical applications, RNA therapeutics are becoming a key part of personalized medicine.


References:

  1. Collotta, D., Bertocchi, I., Chiapello, E., & Collino, M. (2023, November 17). Antisense oligonucleotides: A novel frontier in pharmacological strategy. Frontiers in pharmacology. https://pmc.ncbi.nlm.nih.gov/articles/PMC10690781/ 

  2. Damase TR, Sukhovershin R, Boada C, Taraballi F, Pettigrew RI, Cooke JP. The Limitless Future of RNA Therapeutics. Front Bioeng Biotechnol. 2021 Mar 18;9:628137. doi: 10.3389/fbioe.2021.628137. PMID: 33816449; PMCID: PMC8012680.

  3. Minikel , eric. (2018, July 25). Antisense Part II: Mechanisms of Action. Antisense part II: Mechanisms of action. https://www.cureffi.org/2018/07/25/antisense-part-ii-mechanisms-of-action/ 

  4. MRNA therapeutics: Thermo fisher scientific - US. mRNA Therapeutics | Thermo Fisher Scientific - US. (n.d.). https://www.thermofisher.com/us/en/home/industrial/pharma-biopharma/pharma-biopharma-learning-center/biopharmaceutical-characterization-information/mrna-therapeutics.html 

  5. Redman, M., King, A., Watson, C., & King, D. (2016, August). What is CRISPR/cas9?. Archives of disease in childhood. Education and practice edition. https://pmc.ncbi.nlm.nih.gov/articles/PMC4975809/ 

  6. Roberts, R. (n.d.). CRISPR sgRNA for Successful Gene Editing: Discovery to Clinic. Synthego. https://www.synthego.com/blog/crispr-gmp-sgrna 

  7. Singh, N. N., Luo, D., & Singh, R. N. (2018). Pre-mrna splicing modulation by antisense oligonucleotides. Methods in molecular biology (Clifton, N.J.). https://pmc.ncbi.nlm.nih.gov/articles/PMC6195309/ 

  8. Small interfering RNA. Small Interfering RNA - an overview | ScienceDirect Topics. (n.d.). https://www.sciencedirect.com/topics/medicine-and-dentistry/small-interfering-rna 

  9. Umassmedrti. (2022, January 10). What are RNA therapeutics? RNA Therapeutics Institute at UMass Chan Medical School. UMass Chan Medical School. https://www.umassmed.edu/rti/biology/rna-technology/rna-therapeutics/ 

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