What’s Next: Innovation In Neurology

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Transforming the Management of Neurologic Diseases

Discovering new approaches to manage neurologic diseases can be especially challenging. The current challenges with drug development leave significant unmet clinical needs among these patients.1

Ionis is committed to discovering, developing, and delivering potentially life-changing medicines for people living with severe, progressive, and fatal neurologic diseases.2

The Processes That Play a Role in Many Neurologic Diseases

Neurologic diseases can be caused by genetic variants from a range of proteins.3-6

Over 1700 distinct genetic variants have been identified as contributing to a range of conditions, including neurodegenerative, neuromuscular, and neurodevelopmental diseases.3-6

The types of genetic variants contributing to disease pathology can vary, but generally fall under 1 of 4 categories: point mutations, copy number variants, small insertions and deletions (InDels), and chromosomal rearrangements.7 These can cause disease through altering protein structure and/or production.7

Genetic variants can vary, but generally fall under 1 of 4 categories:

genetic variants diagram

For example, point mutations or InDels in the glial fibrillary acidic protein (GFAP) gene can alter protein accumulation in Alexander disease while Angelman syndrome (AS) is primarily caused (70%) by chromosomal rearrangement causing loss of function of the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene.8-10

Despite advancements in understanding the pathology of neurologic diseases, many are not readily targeted by traditional small molecules or antibody medicines.11

RNA has emerged as a unique target for developing therapeutics due to the broad applicability, translational utility, and efficiency of the drug discovery processes.12,13

Learn more about how RNA-targeted medicines work.

RNA-Targeted Medicines: Innovating What’s Possible

RNA-targeted medicines can target and modulate RNA in the cell, thereby altering protein production, and offer a therapeutic approach for neurological disease, including diseases that may not be amenable to treatment with small molecules or biologics.11,13-19

rna-targeted medicines diagram

RNA-targeted medicines are designed to interact precisely with RNA through Watson-Crick base pairing.14,22 This allows RNA-targeted medicines to target a single disease-associated gene throughout the different tissues and cell types within the central nervous system (CNS).23 RNA-targeted medicines can modulate protein production primarily through the following 2 mechanisms11:

  • mRNA degradation, either through RNase H-mediated or RNA-induced silencing complex (RISC)-mediated degradation
  • Alternative splicing

The effects of RNA-targeted medicines on gene expression are rapid and reversible, and they do not modify a patient’s genome.11,12,22,24


  1. Morant AV, Jagalski V, Vestergaard HT. Labeling of disease-modifying therapies for neurodegenerative disorders. Front Med (Lausanne). 2019;6:223.
  2. Ionis Pharmaceuticals. Ionis Innovation Day. October 4, 2023. Accessed January 31, 2024.
  3. Schüle R, Timmann D, Erasmus CE, et al. Solving unsolved rare neurological diseases-a Solve-RD viewpoint. Eur J Hum Genet. 2021;29(9):1332-1336.
  4. de Rojas I, Moreno-Grau S, Tesi N, et al. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores [published correction appears in Nat Commun. 2023 Feb 9;14(1):716]. Nat Commun. 2021;12(1):3417.
  5. Maranga C, Fernandes TG, Bekman E, da Rocha ST. Angelman syndrome: a journey through the brain. FEBS J. 2020;287(11):2154-2175.
  6. Picher-Martel V, Brunet F, Dupré N, Chrestian N. The occurrence of FUS mutations in pediatric amyotrophic lateral sclerosis: a case report and review of the literature. J Child Neurol. 2020;35(8):556-562.
  7. Ku CS, Loy EY, Salim A, Pawitan Y, Chia KS. The discovery of human genetic variations and their use as disease markers: past, present and future. J Hum Genet. 2010;55(7):403-415.
  8. Messing A. Alexander disease. Handb Clin Neurol. 2018;148:693-700.
  9. Khan N, Cabo R, Tan WH, et al. Healthcare burden among individuals with Angelman syndrome: findings from the Angelman Syndrome Natural History Study. Mol Genet Genomic Med. 2019;7(7):e00734.
  10. Harewood L, Fraser P. The impact of chromosomal rearrangements on regulation of gene expression. Hum Mol Genet. 2014;23(R1):R76-82.
  11. Bennett CF, Krainer AR, Cleveland DW. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu Rev Neurosci. 2019;42:385-406. 2021;296:100416.
  12. Crooke ST, Liang XH, Baker BF, Crooke RM. Antisense technology: a review. J Biol Chem. 2021;296:100416.
  13. Data on file. Ionis Pharmaceuticals.
  14. Chery J. RNA therapeutics: RNAi and antisense mechanisms and clinical applications. Postdoc J. 2016;4(7):35-50.
  15. Poplawski SG, Garbett KA, McMahan RL, et al. An antisense oligonucleotide leads to suppressed transcription of Hdac2 and long-term memory enhancement. Mol Ther Nucleic Acids. 2020;19:1399-1412.
  16. Coleman N, Rodon J. Taking aim at the undruggable. Am Soc Clin Oncol Educ Book. 2021;41:1-8.
  17. Crooke ST, Baker BF, Crooke RM, Liang XH. Antisense technology: an overview and prospectus. Nat Rev Drug Discov. 2021;20(6):427-453.
  18. Roberts TC, Langer R, Wood MJA. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov. 2020;19(10):673-694.
  19. Yu AM, Jian C, Yu AH, Tu MJ. RNA therapy: are we using the right molecules? Pharmacol Ther. 2019;196:91-104.
  20. Martier R, Konstantinova P. Gene therapy for neurodegenerative diseases: slowing down the ticking clock. Front Neurosci. 2020;14:580179.
  21. Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1-2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2020;383(2):109-119.
  22. 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.
  23. Jafar-Nejad P, Powers B, Soriano A, et al. The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration. Nucleic Acids Res. 2021;49(2):657-673.
  24. 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.

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