Ionis Neurology: Pipeline

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Ionis continues to build upon its pioneering platform and foundational knowledge to develop medicines that can alter disease trajectory.1-4

Transforming Genomic Insights Into RNA-Targeted Innovation

Ionis’ RNA-targeted technology translates genomics insights into potential transformative medicines.5

Once a causative gene is identified, researchers can use this knowledge to develop antisense oligonucleotides (ASOs) that target the associated mRNA and modulate protein production.4,6,7 Ionis has used knowledge from the genomics revolution to develop FDA-approved medicines for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), and polyneuropathy in patients with hereditary transthyretin (hATTR) amyloidosis.7-13

Case Study: SMA

Prior to the 1990s, the fundamental cause of SMA was unknown.7,14 Research throughout the 1990s identified the cause of SMA—the deletion of survival motor neuron gene 1 (SMN1)—and a potential therapeutic target: alternative splicing to include exon 7 of SMN2.7,9

ASOs were screened for the optimal target along exon 7 of SMN2, marking a shift in drug discovery.5,7-9,15

Ionis development timeline chart
ASO, antisense oligonucleotide; FDA, US Food and Drug Administration; RTM, RNA-targeted medicine; SMA, spinal muscular atrophy.

Identifying the Neurologic Medicines of Tomorrow

Years of preclinical studies have yielded a rigorous process to optimize the identification and development of RNA-targeted medicines with reduced toxicity and a potentially favorable safety and tolerability profile for patients with neurologic diseases.1,3,16-19

Ionis is continually advancing the design, screening rigor, and development of its RNA-targeted medicines to optimize the selection of investigational medicines.1,3,18

Ionis Is Continually Advancing the Design, Screening, and Development of Its Investigational RNA-Targeted Medicines for Neurologic Diseases1,3,18,19

MD, multiple dose; SD, single dose.






Click on the figure above to learn more about the rigorous screening process that allows the identification of an investigational RNA-targeted medicine from thousands of oligonucleotides.18,19

Ionis is continually refining and optimizing its RNA-targeted medicine platform to positively impact the lives of patients with neurologic diseases, creating new standards of care.24


  1. Crooke ST, Liang XH, Baker BF, Crooke RM. Antisense technology: A review. J Biol Chem. 2021;296:100416.
  2. Ionis Pharmaceuticals. Annual Report 2022. Accessed January 31, 2024.
  3. 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.
  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. Bennett CF, Krainer AR, Cleveland DW. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu Rev Neurosci. 2019;42:385-406.
  7. Qiu J, Wu L, Qu R, et al. History of development of the life-saving drug “Nusinersen” in spinal muscular atrophy. Front Cell Neurosci. 2022;16:942976.
  8. 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.
  9. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet. 2008;82(4):834-848.
  10. FDA approves first drug for spinal muscular atrophy. US Food and Drug Administration. December 23, 2016. Accessed February 5, 2024.
  11. AstraZeneca. Press releases. December 7, 2021. Accessed February 5, 2024.
  12. Wainua. Package insert. AstraZeneca; December 2023. Accessed February 5, 2024.
  13. Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110.
  14. Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015;33(4):831-846.
  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. identifier: NCT01494701. Accessed February 5, 2024.
  16. Bajan S, Hutvagner G. RNA-based therapeutics: from antisense oligonucleotides to miRNAs. Cells. 2020;9(1):137.
  17. Shen W, De Hoyos CL, Migawa MT, et al. Chemical modification of PS-ASO therapeutics reduces cellular protein-binding and improves the therapeutic index. Nat Biotechnol. 2019;37(6):640-650.
  18. Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-targeted therapeutics. Cell Metab. 2018;27(4):714-739.
  19. Ionis Pharmaceuticals. Data on file.
  20. Crooke ST, Vickers TA, Liang XH. Phosphorothioate modified oligonucleotide-protein interactions. Nucleic Acids Res. 2020;48(10):5235-5253.
  21. Chang JL, Hinrich AJ, Roman B, et al. Targeting amyloid-β precursor protein, APP, splicing with antisense oligonucleotides reduces toxic amyloid-β production. Mol Ther. 2018;26(6):1539-1551.
  22. Kher G, Trehan S, Misra A. Antisense oligonucleotides and RNA interference. In: Misra A, ed. Challenges in Delivery of Therapeutic Genomics and Proteomics. Elsevier; 2011:325-386.
  23. Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19(10):673-694.
  24. Ionis Pharmaceuticals. The Ionis antisense pipeline. Accessed February 5, 2024.

Contact Us

For questions or to request information, please contact us.

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Ionis is built on a foundation of transformative technologies that target the underlying causes of neurologic diseases.

Learn more about innovation in neurology »

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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