What’s Next: Innovation In Neurology

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RNA-Targeted Regulation of Proteins

There are different classes of RNA-targeted medicines, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs).1

ASOs are single-strand oligonucleotides that bind directly to their mRNA target to upregulate or downregulate protein production by either1-4:

  • Preventing protein translation through RNase H-mediated degradation of the heteroduplex (ie, RNA-targeted medicine–[pre-]mRNA duplex)
  • Regulating gene expression via heteroduplex-induced alternative splicing, which includes exon skipping or inclusion
Antisense Oligonucleotides diagram
dsDNA, double-stranded DNA; mRNA, messenger RNA; RTM, RNA-targeted medicine.

siRNAs are double-strand oligonucleotides that associate with the RNA-induced silencing complex (RISC) to bind the complementary target RNA, leading to altered protein production via mRNA cleavage or association-mediated repression.1,3,4

 siRNAs diagram
dsDNA, double-stranded DNA; mRNA, messenger RNA; siRNA, small interfering RNA.

The molecular mechanisms through which RNA-targeted medicines modulate RNA function are dependent on the chemical modifications, the position of the modifications, and the location of the binding site on the target RNA.6

Creators of Trail-Blazing Innovation

Ionis created the chemistry behind RNA-targeted, FDA-approved, and investigational medicines and has spent decades advancing its platform.5,7-9

Ionis developing therapies timeline chart
FDA, US Food and Drug Administration.

Ionis is a leader in developing transformational RNA-targeted medicines for neurologic diseases. Ionis advances include1,3,7,21-23:

  • Developing the chemistry that is used as the basis for commercialized RNA-targeted medicines | Learn more
  • Creating iterative screening and refining processes to identify RNA-targeted medicines for clinical settings | Learn more
  • Innovating targeted tissue delivery and systemic delivery for RNA-targeted medicines
  • Pioneering mechanisms to modulate gene expression

The success of nusinersen, eplontersen, and tofersen—all Ionis-originated, FDA-approved medicines—are examples of our ability to provide potentially life-changing options to patients with a neurologic disease.4,5,10,11,24

Taking RNA-Targeted Medicines Further

RNA-targeted medicines are designed to modulate mRNA in a highly specific manner. A comparative study of the efficacy, potency, and specificity of RNA-targeted medicines in a human cell culture assay found that as little as 2 base mismatches were enough to reduce RNA-targeted medicine activity.25

RNA-targeted medicine behavior can be modulated through chemical modifications, which has the potential to improve characteristics such as the potency, safety, and tolerability profiles.3,20,21

Optimization of RNA-targeted medicines at Ionis has led to20,21:

  • Delivery to multiple tissue types
  • Increased dose flexibility
  • Increased safety and tolerability
  • Decreased dose volume
  • Increased potency

Click on the following figure to learn more about some of the pioneering biochemical discoveries behind the development of some of the first-in-class RNA-targeted medicines developed at Ionis.20

Modifications at the ribose position enhance the pharmacological profile and protein binding of investigational RNA-targeted medicines1,3-5,13,20

Ionis pioneered the discovery and development of modifications to the oligonucleotide backbone of investigational RNA-targeted medicines1,3-5,13,20,21,26

Molecular diagram



A, adenine; C, cytosine; G, guanine; T, thymine.


  1. Crooke ST, Liang XH, Baker BF, Crooke RM. Antisense technology: a review. J Biol Chem. 2021;296:100416.
  2. Dhuri K, Bechtold C, Quijano E, et al. Antisense oligonucleotides: an emerging area in drug discovery and development. J Clin Med. 2020;9(6):2004.
  3. Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-targeted therapeutics. Cell Metab. 2018;27(4):714-739.
  4. Bennett CF, Kordasiewicz HB, Cleveland DW. Antisense drugs make sense for neurological diseases. Annu Rev Pharmacol Toxicol. 2021;61:831-852.
  5. Crooke ST, Baker BF, Crooke RM, Liang XH. Antisense technology: an overview and prospectus. Nat Rev Drug Discov. 2021;20(6):427-453.
  6. Watts JK, Corey DR. Silencing disease genes in the laboratory and the clinic. J Pathol. 2012;226(2):365-379.
  7. Crooke ST. RNA-directed therapeutics at Ionis. Nature. 2019;574(7778):1-3.
  8. Bajan S, Hutvagner G. RNA-based therapeutics: from antisense oligonucleotides to miRNAs. Cells. 2020;9(1):137.
  9. Dhuri K, Bechtold C, Quijano E, et al. Antisense oligonucleotides: an emerging area in drug discovery and development. J Clin Med. 2020;9(6):2004.
  10. Qalsody. Package insert. Biogen MA Inc. Updated April 2023. Accessed February 5, 2024.
  11. Wainua. Package insert. AstraZeneca; December 2023. Accessed February 5, 2024.
  12. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR. Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol. 2007;5(4):e73.
  13. Bennett CF, Krainer AR, Cleveland DW. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu Rev Neurosci. 2019;42:385-406.
  14. A phase 1, double-blind, placebo-controlled, dose-escalation study of the safety, tolerability, and pharmacokinetics of ISIS 333611 administered intrathecally to patients with familial amyotrophic lateral sclerosis due to superoxide dismutase 1 gene mutations. ClinicalTrials.gov identifier: NCT01041222. Accessed February 5, 2024.
  15. An open-label, escalating dose study to assess the safety, tolerability and dose-range finding of a single intrathecal dose of ISIS 396443 in patients with spinal muscular atrophy. ClinicalTrials.gov identifier: NCT01494701. Accessed February 5, 2024.
  16. Ionis Pharmaceuticals. Press releases. December 21, 2010; December 10, 2012. Accessed February 5, 2024.
  17. Biogen. Press release. December 6, 2018. Accessed February 5, 2024.
  18. Evaluate the safety and tolerability, as well as the pharmacokinetic and pharmacodynamic profiles of single and multiple doses of eplontersen administered subcutaneously to healthy volunteers and patients with hereditary transthyretin-mediated amyloidosis (hATTR ). ClinicalTrials.gov identifier: NCT03728634. Accessed February 5, 2024.
  19. AstraZeneca. Press releases. December 7, 2021. Accessed February 5, 2024.
  20. Data on file. Ionis Pharmaceuticals.
  21. Ionis Pharmaceuticals. Ionis Innovation Day. October 4, 2023. Accessed February 5, 2024.
  22. Ionis Pharmaceuticals. Ionis antisense technology. Accessed February 5, 2024.
  23. Partridge W, Xia S, Kwoh TJ, Bhanot S, Geary RS, Baker BF. Improvements in the tolerability profile of 2′-O-methoxyethyl chimeric antisense oligonucleotides in parallel with advances in design, screening, and other methods. Nucleic Acid Ther. 2021;31(6):417-426.
  24. Ionis Pharmaceuticals. Our antisense medicines. Accessed March 13, 2024.
  25. Vickers TA, Koo S, Bennett CF, Crooke ST, Dean NM, Baker BF. Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J Biol Chem. 2003;278(9):7108-7118.
  26. Crooke ST, Vickers TA, Liang XH. Phosphorothioate modified oligonucleotide-protein interactions. Nucleic Acids Res. 2020;48(10):5235-5253.

Contact Us

For questions or to request information, please contact us.

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Ionis continues to build upon its pioneering platform and foundational knowledge to develop medicines that can alter disease trajectory.

Learn more about the Ionis pipeline and candidates »

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We are committed to addressing the significant unmet needs across a spectrum of neurologic diseases.

Learn more about Ionis’ involvement in the community »

US-GEN-2400029 v1.0 03/2024