Antisense therapy

From Wikipedia, the free encyclopedia

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA.[1] Several ASOs have been approved in the United States, the European Union, and elsewhere.


The common stem for antisense oligonucleotides drugs is -rsen. The substem -virsen designates antiviral antisense oligonucleotides.[2]

Pharmacokinetics and pharmacodynamics[edit]

Half-life and stability[edit]

ASO-based drugs employ highly modified, single-stranded chains of synthetic nucleic acids that achieve wide tissue distribution with very long half-lives.[3][4][5] For instance, many ASO-based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit nuclease degradation enabling vehicle-free delivery to cells.[6][7]

In vivo delivery[edit]

Phosphorothioate ASOs can be delivered to cells without the need of a delivery vehicle. ASOs do not penetrate the blood brain barrier when delivered systemically but they can distribute across the neuraxis if injected in the cerebrospinal fluid typically by intrathecal administration. Newer formulations using conjugated ligands greatly enhances delivery efficiency and cell-type specific targeting.[6]

Approved therapies[edit]

Amyotrophic lateral sclerosis[edit]

Tofersen (marketed as Qalsody) was approved by the FDA for the treatment of SOD1- associated amyotrophic lateral sclerosis (ALS) in 2023.[8] It was developed by Biogen under a licensing agreement with Ionis Pharmaceuticals. In trials the drug was found to lower levels of an ALS biomarker, neurofilament light change, and in long-term trial extensions to slow disease.[8] Under the terms of the FDA's accelerated approval program, a confirmatory study will be conducted in presymptomatic gene carriers to provide additional evidence.[9]

Batten disease[edit]

Milasen is a novel individualized therapeutic agent that was designed and approved by the FDA for the treatment of Batten disease. This therapy serves as an example of personalized medicine.[10][11]

In 2019, a report was published detailing the development of milasen, an antisense oligonucleotide drug for Batten disease, under an expanded-access investigational clinical protocol authorized by the Food and Drug Administration (FDA).[10] Milasen "itself remains an investigational drug, and it is not suited for the treatment of other patients with Batten's disease" because it was customized for a single patient's specific mutation.[10] However it is an example of individualized genomic medicine therapeutical intervention.[10][12]

Cytomegalovirus retinitis[edit]

Fomivirsen (marketed as Vitravene), was approved by the U.S. FDA in August 1998, as a treatment for cytomegalovirus retinitis.[13]

Duchenne muscular dystrophy[edit]

Several morpholino oligos have been approved to treat specific groups of mutations causing Duchenne muscular dystrophy. In September 2016, eteplirsen (ExonDys51) received FDA approval[14] for the treatment of cases that can benefit from skipping exon 51 of the dystrophin transcript. In December 2019, golodirsen (Vyondys 53) received FDA approval[15] for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript. In August 2020, viltolarsen (Viltepso) received FDA approval for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript.[16]

Familial chylomicronaemia syndrome[edit]

Volanesorsen was approved by the European Medicines Agency (EMA) for the treatment of familial chylomicronaemia syndrome in May 2019.[17][18]

Familial hypercholesterolemia[edit]

In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia. [19][20][21]

Hereditary transthyretin-mediated amyloidosis[edit]

Inotersen received FDA approval for the treatment of hereditary transthyretin-mediated amyloidosis in October 2018.[22] The application for inotersen was granted orphan drug designation.[22] It was developed by Ionis Pharmaceuticals and licensed to Akcea Therapeutics. Patisiran (sold under Onpattro) was developed by Alnylam Pharmaceuticals, and also approved for use in the US and EU in 2018 with orphan drug designation.[23] Its mechanism-of-action is the active substance of small interfering RNA (siRNA), which allows it to interfere with and block the production of trasnthyretin.[24] As such, it was the first FDA-approved siRNA therapeutic.[23]

Spinal muscular atrophy[edit]

In 2004, development of an antisense therapy for spinal muscular atrophy began. Over the following years, an antisense oligonucleotide later named nusinersen was developed by Ionis Pharmaceuticals under a licensing agreement with Biogen. In December 2016, nusinersen received regulatory approval from FDA[25][26] and soon after, from other regulatory agencies worldwide.

Investigational therapies[edit]

Current clinical trials[edit]

As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 25 in advanced clinical trials (phase II or III).[27][28]

Phase III trials[edit]

Hereditary transthyretin-mediated amyloidosis[edit]

A follow-on drug to Inotersen is being developed by Ionis Pharmaceuticals and under license to Akcea Therapeutics for hereditary transthyretin-mediated amyloidosis. In this formulation the ASO is conjugated to N-Acetylgalactosamine enabling hepatocyte-specific delivery, greatly reducing dose requirements and side effect profile while increasing the level of transthyretin reduction in patients.

Huntington's disease[edit]

Tominersen (also known as IONIS-HTTRx and RG6042) was tested in a phase 3 trial for Huntington's disease[29] although this trial was discontinued on March 21, 2021, due to lack of efficacy.[30] It is currently licensed to Roche by Ionis Pharmaceuticals.

Phase I and II trials[edit]

Clinical trials are ongoing for several diseases and conditions including:

Acromegaly, age related macular degeneration, Alzheimer's disease, amyotrophic lateral sclerosis, autosomal dominant retinitis pigmentosa, beta thalassemia, cardiovascular disease, elevated level of lipoprotein(a),[31] centronuclear myopathy, coagulopathies, cystic fibrosis, Duchenne muscular dystrophy, diabetes, epidermolysis bullosa dystrophica, familial chylomicronemia syndrome, frontotemporal dementia, Fuchs' dystrophy, hepatitis B, hereditary angioedema, hypertension, IgA nephropathy, Leber's hereditary optic neuropathy, multiple system atrophy, non-alcoholic fatty liver disease, Parkinson's disease, prostate cancer, Stargardt disease, STAT3-expressing cancers, Usher syndrome.

Preclinical development[edit]

Several ASOs are currently being investigated in disease models for Alexander disease,[32] ATXN2 (gene) and FUS (gene) amyotrophic lateral sclerosis, Angelman syndrome,[33] Lafora disease, lymphoma, multiple myeloma, myotonic dystrophy, Parkinson's disease,[34] Pelizaeus–Merzbacher disease,[35][36] and prion disease,[37] Rett syndrome,[38] spinocerebellar Ataxia Type 3.

See also[edit]


  1. ^ Morcos PA (June 2007). "Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino oligos". Biochemical and Biophysical Research Communications. 358 (2): 521–7. doi:10.1016/j.bbrc.2007.04.172. PMID 17493584.
  2. ^ International Nonproprietary Names (INN) for biological and biotechnological substances
  3. ^ Weiss, B. (ed.): Antisense Oligodeoxynucleotides and Antisense RNA : Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997. ISBN 0849385520 ISBN 9780849385520
  4. ^ Weiss B, Davidkova G, Zhou LW (March 1999). "Antisense RNA technology for studying and modulating biological processes". Cellular and Molecular Life Sciences. 55 (3): 334–58. doi:10.1007/s000180050296. PMID 10228554. S2CID 9448271.
  5. ^ Goodchild J (2011). "Therapeutic Oligonucleotides". Methods in Molecular Biology. Vol. 764. pp. 1–15. doi:10.1007/978-1-61779-188-8_1. ISBN 978-1-61779-187-1. PMID 21748630. {{cite book}}: Missing or empty |title= (help)
  6. ^ a b Bennett CF, Swayze EE (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annual Review of Pharmacology and Toxicology. 50: 259–93. doi:10.1146/annurev.pharmtox.010909.105654. PMID 20055705.
  7. ^ Xu L, Anchordoquy T (January 2011). "Drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics". Journal of Pharmaceutical Sciences. 100 (1): 38–52. doi:10.1002/jps.22243. PMC 3303188. PMID 20575003.
  8. ^ a b "Tofersen". The ALS Association. Retrieved 2023-04-25.
  9. ^ Research, Center for Drug Evaluation and (2023-04-25). "FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene". FDA.
  10. ^ a b c d Kim, Jinkuk; Hu, Chunguang; Moufawad El Achkar, Christelle; Black, Lauren E.; Douville, Julie; Larson, Austin; Pendergast, Mary K.; Goldkind, Sara F.; Lee, Eunjung A.; Kuniholm, Ashley; Soucy, Aubrie (2019-10-09). "Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease". New England Journal of Medicine. 381 (17): 1644–1652. doi:10.1056/NEJMoa1813279. ISSN 0028-4793. PMC 6961983. PMID 31597037.
  11. ^ Gallagher, James (2019-10-12). "Unique drug for a girl with deadly brain disease". Retrieved 2019-10-14.
  12. ^ "A Drug Was Made For Just One Child, Raising Hopes About Future Of Tailored Medicine". Retrieved 2019-10-14.
  13. ^ "Drug Approval Package: Vitravene (Fomivirsen Sodium Intravitreal Injectable) NDA# 20-961". U.S. Food and Drug Administration (FDA). Retrieved 22 September 2020.
  14. ^ U.S. Food and Drug Administration, Silver Springs, Maryland. News Release: FDA grants accelerated approval to first drug for Duchenne muscular dystrophy, September 19, 2016. Archived August 2, 2019, at the Wayback Machine
  15. ^ "FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation". U.S. Food and Drug Administration (FDA) (Press release). 12 December 2019. Archived from the original on 13 December 2019. Retrieved 12 December 2019.
  16. ^ "FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation". U.S. Food and Drug Administration (FDA) (Press release). 12 August 2020. Retrieved 12 August 2020.
  17. ^ "Akcea and Ionis Announce Approval of Waylivra (volanesorsen) in the European Union" (Press release). Akcea Therapeutics. 7 May 2019. Retrieved 22 September 2020 – via GlobeNewswire.
  18. ^ "Waylivra EPAR". European Medicines Agency (EMA). 24 September 2018. Retrieved 22 September 2020.
  19. ^ "Drug Approval Package: Kynamro (mipomersen sodium) Injection NDA #203568". U.S. Food and Drug Administration (FDA). Retrieved 22 September 2020.
  20. ^ Pollack A (29 January 2013). "F.D.A. Approves Genetic Drug to Treat Rare Disease". The New York Times.
  21. ^ "FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder". Fierce Biotech. 29 January 2013. Retrieved 7 March 2021.
  22. ^ a b "Inotersen Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 24 July 2012. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  23. ^ a b "FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease". Case Medical Research. 2018-08-10. doi:10.31525/fda2-ucm616518.htm. ISSN 2643-4652. S2CID 240302876.
  24. ^ Kristen, Arnt V; Ajroud-Driss, Senda; Conceição, Isabel; Gorevic, Peter; Kyriakides, Theodoros; Obici, Laura (2019-02-01). "Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis". Neurodegenerative Disease Management. 9 (1): 5–23. doi:10.2217/nmt-2018-0033. ISSN 1758-2024. PMID 30480471. S2CID 53756758.
  25. ^ Wadman M (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science. doi:10.1126/science.aal0476.
  26. ^ Grant C (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
  27. ^ Bennett CF, Swayze EE (2010). "RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform". Annual Review of Pharmacology and Toxicology. 50: 259–93. doi:10.1146/annurev.pharmtox.010909.105654. PMID 20055705.
  28. ^ Watts JK, Corey DR (January 2012). "Silencing disease genes in the laboratory and the clinic". The Journal of Pathology. 226 (2): 365–79. doi:10.1002/path.2993. PMC 3916955. PMID 22069063.
  29. ^ Miller, Timothy; Cudkowicz, Merit; Shaw, Pamela J.; Andersen, Peter M.; Atassi, Nazem; Bucelli, Robert C.; Genge, Angela; Glass, Jonathan; Ladha, Shafeeq; Ludolph, Albert L.; Maragakis, Nicholas J. (2020-07-09). "Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS". New England Journal of Medicine. 383 (2): 109–119. doi:10.1056/NEJMoa2003715. ISSN 0028-4793. PMID 32640130.
  30. ^ "Roche drops Huntington's disease trial with once-promising drug tominersen". Reuters. 2021-03-23. Retrieved 2021-03-25.
  31. ^ Langsted, Anne; Nordestgaard, Børge G. (2019-05-20). "Antisense Oligonucleotides Targeting Lipoprotein(a)". Current Atherosclerosis Reports. 21 (8): 30. doi:10.1007/s11883-019-0792-8. ISSN 1534-6242. PMID 31111240. S2CID 160014574.
  32. ^ Hagemann, Tracy L.; Powers, Berit; Mazur, Curt; Kim, Aneeza; Wheeler, Steven; Hung, Gene; Swayze, Eric; Messing, Albee (2018). "Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease". Annals of Neurology. 83 (1): 27–39. doi:10.1002/ana.25118. ISSN 1531-8249. PMC 5876100. PMID 29226998.
  33. ^ Meng, Linyan; Ward, Amanda J.; Chun, Seung; Bennett, C. Frank; Beaudet, Arthur L.; Rigo, Frank (February 2015). "Towards a therapy for Angelman syndrome by targeting a long non-coding RNA". Nature. 518 (7539): 409–412. Bibcode:2015Natur.518..409M. doi:10.1038/nature13975. ISSN 1476-4687. PMC 4351819. PMID 25470045.
  34. ^ Qian, Hao; Kang, Xinjiang; Hu, Jing; Zhang, Dongyang; Liang, Zhengyu; Meng, Fan; Zhang, Xuan; Xue, Yuanchao; Maimon, Roy; Dowdy, Steven F.; Devaraj, Neal K. (June 2020). "Reversing a model of Parkinson's disease with in situ converted nigral neurons". Nature. 582 (7813): 550–556. Bibcode:2020Natur.582..550Q. doi:10.1038/s41586-020-2388-4. ISSN 1476-4687. PMC 7521455. PMID 32581380. S2CID 220051280.
  35. ^ Elitt, Matthew S.; Barbar, Lilianne; Shick, H. Elizabeth; Powers, Berit E.; Maeno-Hikichi, Yuka; Madhavan, Mayur; Allan, Kevin C.; Nawash, Baraa S.; Gevorgyan, Artur S.; Hung, Stevephen; Nevin, Zachary S. (2020-07-01). "Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease". Nature. 585 (7825): 397–403. Bibcode:2020Natur.585..397E. doi:10.1038/s41586-020-2494-3. ISSN 1476-4687. PMC 7810164. PMID 32610343. S2CID 220309225.
  36. ^ "Research finds new approach to treating certain neurological diseases". Retrieved 2020-07-23.
  37. ^ Raymond, Gregory J.; Zhao, Hien Tran; Race, Brent; Raymond, Lynne D.; Williams, Katie; Swayze, Eric E.; Graffam, Samantha; Le, Jason; Caron, Tyler; Stathopoulos, Jacquelyn; O'Keefe, Rhonda (2019-08-22). "Antisense oligonucleotides extend survival of prion-infected mice". JCI Insight. 4 (16). doi:10.1172/jci.insight.131175. ISSN 0021-9738. PMC 6777807. PMID 31361599.
  38. ^ Sztainberg, Yehezkel; Chen, Hong-mei; Swann, John W.; Hao, Shuang; Tang, Bin; Wu, Zhenyu; Tang, Jianrong; Wan, Ying-Wooi; Liu, Zhandong; Rigo, Frank; Zoghbi, Huda Y. (December 2015). "Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides". Nature. 528 (7580): 123–126. Bibcode:2015Natur.528..123S. doi:10.1038/nature16159. ISSN 1476-4687. PMC 4839300. PMID 26605526.

External links[edit]