antisense therapy

The common stem for antisense oligonucleotides drugs is -rsen. The substem -virsen designates antiviral antisense oligonucleotides.{{Cite web |title=INN Bio Review 2022 |url=https://www.who.int/publications/m/item/who-mhp-hps-inn-2022-2 |access-date=2024-08-05 |website=www.who.int |language=en}}

Developments in ASO modification are separated into three generations.{{cite journal |last1=Çakan |first1=Elif |title=Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside |journal=Cancers |date=2024 |volume=16 |issue=17 |page=2940 |doi=10.3390/cancers16172940 |doi-access=free |pmid=39272802 |pmc=11394571 }} Generation one is called backbone-modified and focuses on the phosphodiester group of the nucleotide. This impacts inter-nucleotide binding. These modifications led to better distribution, reduced urinary excretion, and prolonged residence time of the ASOs in the cell. Some examples of first generation modifications include the addition of a phosphorothioate group (PS), methyl group, or nitrogen. The most common is the phosphorothioate group (PS) in which the oxygen atoms of a phosphodiester group are replaced with sulfur atoms, greatly improving efficacy and reducing degradation. Generation two is sugar-modified, focused on the ribose sugar of the nucleotide. This generation saw improved binding affinity while reducing degradation. Some examples of generation two modifications are the substitution of R group with morpholine group (MO) and the usage of phosphorodiamidate morpholino oligomer (PMO) and thiomorpholine oligomer (TMO) as linkages between the ribose sugar and phosphodiester group in the backbone. Generation three is nucleobase-modified, the least common type of modification. These modifications enhanced binding affinity and cell penetration while reducing degradation and off-target effects. Examples include the introduction of G-clamps, pseudoisocytosine, and the substitution of bases with amine, thione, halogen, alkyl, alkenyl, or alkynyl groups.{{cite journal |last1=Çakan |first1=Elif |title=Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside |journal=Cancers |date=2024 |volume=16 |issue=17 |page=2940 |doi=10.3390/cancers16172940 |doi-access=free |pmid=39272802 |pmc=11394571 }}

ASO-based drugs employ highly modified, single-stranded chains of synthetic nucleic acids that achieve wide tissue distribution with very long half-lives.Weiss, B. (ed.): Antisense Oligodeoxynucleotides and Antisense RNA : Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997. {{ISBN|0849385520}} {{ISBN|9780849385520}}{{cite journal|vauthors=Weiss B, Davidkova G, Zhou LW|date=March 1999|title=Antisense RNA technology for studying and modulating biological processes|journal=Cellular and Molecular Life Sciences|volume=55|issue=3|pages=334–58|doi=10.1007/s000180050296|pmid=10228554|s2cid=9448271|pmc=11146801}}{{Cite book |last=Goodchild |first=John |chapter=Therapeutic Oligonucleotides |chapter-url=https://link.springer.com/10.1007/978-1-61779-188-8_1 |date=2011 |publisher=Humana Press |isbn=978-1-61779-187-1 |editor-last=Goodchild |editor-first=John |series=Methods in Molecular Biology |volume=764 |location=Totowa, NJ |pages=1–15 |language=en |doi=10.1007/978-1-61779-188-8_1 |pmid=21748630}} For instance, many ASO-based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit nuclease degradation enabling vehicle-free delivery to cells.{{cite journal|vauthors=Bennett CF, Swayze EE|date=2010|title=RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform|journal=Annual Review of Pharmacology and Toxicology|volume=50|pages=259–93|doi=10.1146/annurev.pharmtox.010909.105654|pmid=20055705}}{{cite journal|vauthors=Xu L, Anchordoquy T|date=January 2011|title=Drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics|journal=Journal of Pharmaceutical Sciences|volume=100|issue=1|pages=38–52|doi=10.1002/jps.22243|pmc=3303188|pmid=20575003}}

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.

Tofersen (marketed as Qalsody) was approved by the FDA for the treatment of SOD1- associated amyotrophic lateral sclerosis (ALS) in 2023.{{Cite web |title=Tofersen |url=https://www.als.org/navigating-als/living-with-als/fda-approved-drugs/tofersen |access-date=2023-04-25 |website=The ALS Association |language=en}} 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. Under the terms of the FDA's accelerated approval program, a confirmatory study will be conducted in presymptomatic gene carriers to provide additional evidence.{{Cite journal |last=Research |first=Center for Drug Evaluation and |date=2023-04-25 |title=FDA approves treatment of amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene |url=https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene |archive-url=https://web.archive.org/web/20230425172813/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene |url-status=dead |archive-date=April 25, 2023 |journal=FDA |language=en}}

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.{{Cite journal|last1=Kim|first1=Jinkuk|last2=Hu|first2=Chunguang|last3=Moufawad El Achkar|first3=Christelle|last4=Black|first4=Lauren E.|last5=Douville|first5=Julie|last6=Larson|first6=Austin|last7=Pendergast|first7=Mary K.|last8=Goldkind|first8=Sara F.|last9=Lee|first9=Eunjung A.|last10=Kuniholm|first10=Ashley|last11=Soucy|first11=Aubrie|date=2019-10-09|title=Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease|journal=New England Journal of Medicine|volume=381|issue=17|pages=1644–1652|doi=10.1056/NEJMoa1813279|issn=0028-4793|pmc=6961983|pmid=31597037}}{{Cite news|last=Gallagher|first=James|date=2019-10-12|title=Unique drug for a girl with deadly brain disease|language=en-GB|url=https://www.bbc.com/news/health-49959738|access-date=2019-10-14}}

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). 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. However it is an example of individualized genomic medicine therapeutical intervention.{{Cite web|title=A Drug Was Made For Just One Child, Raising Hopes About Future Of Tailored Medicine|url=https://www.wbur.org/commonhealth/2019/10/11/designer-genetic-drug-therapy-milasen|access-date=2019-10-14|website=www.wbur.org|language=en}}

Fomivirsen (marketed as Vitravene), was approved by the U.S. FDA in August 1998, as a treatment for cytomegalovirus retinitis.{{cite web | title=Drug Approval Package: Vitravene (Fomivirsen Sodium Intravitreal Injectable) NDA# 20-961 | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20961_Vitravene.cfm | archive-url=https://web.archive.org/web/20140310005950/http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20961_Vitravene.cfm | url-status=dead | archive-date=March 10, 2014 | access-date=22 September 2020}}

Several morpholino oligos have been approved to treat specific groups of mutations causing Duchenne muscular dystrophy. In September 2016, eteplirsen (ExonDys51) received FDA approval[https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-drug-duchenne-muscular-dystrophy 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.] {{webarchive|url=https://web.archive.org/web/20190802060217/https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-drug-duchenne-muscular-dystrophy|date=August 2, 2019}} 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{{cite press release | title=FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation | website=U.S. Food and Drug Administration (FDA) | date=12 December 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation | archive-url=https://web.archive.org/web/20191213043443/https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation | archive-date=13 December 2019 | url-status=dead | access-date=12 December 2019}} 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.{{cite press release | title=FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation | website=U.S. Food and Drug Administration (FDA) | date=12 August 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation | archive-url=https://web.archive.org/web/20200820041846/https://www.fda.gov/news-events/press-announcements/fda-approves-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation | url-status=dead | archive-date=August 20, 2020 | access-date=12 August 2020}}

Volanesorsen was approved by the European Medicines Agency (EMA) for the treatment of familial chylomicronaemia syndrome in May 2019.{{cite press release | publisher=Akcea Therapeutics | title=Akcea and Ionis Announce Approval of Waylivra (volanesorsen) in the European Union | via=GlobeNewswire | date=7 May 2019 | url=http://www.globenewswire.com/news-release/2019/05/07/1818393/0/en/Akcea-and-Ionis-Announce-Approval-of-WAYLIVRA-volanesorsen-in-the-European-Union.html | access-date=22 September 2020}}{{cite web | title=Waylivra EPAR | website=European Medicines Agency (EMA) | date=24 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/waylivra | access-date=22 September 2020}}

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

{{cite web | title=Drug Approval Package: Kynamro (mipomersen sodium) Injection NDA #203568 | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203568Orig1s000TOC.cfm | access-date=22 September 2020}}

• {{cite web|title = Summary Report|url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203568Orig1s000SumR.pdf }}{{cite news | last = Pollack | first = Andrew | name-list-style = vanc | date = 29 January 2013 | url = https://www.nytimes.com/2013/01/30/business/fda-approves-genetic-drug-to-treat-rare-disease.html | title = F.D.A. Approves Genetic Drug to Treat Rare Disease | work = The New York Times }}{{cite news |author= |title=FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder |url=https://www.fiercebiotech.com/biotech/fda-approves-new-orphan-drug-kynamro-to-treat-inherited-cholesterol-disorder |work=Fierce Biotech |date=29 January 2013 |access-date=7 March 2021}}

Inotersen received FDA approval for the treatment of hereditary transthyretin-mediated amyloidosis in October 2018. The application for inotersen was granted orphan drug designation.{{cite web | title=Inotersen Orphan Drug Designation and Approval | website=U.S. Food and Drug Administration (FDA) | date=24 July 2012 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=374512 | archive-url=https://web.archive.org/web/20191219053120/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=374512 | archive-date=19 December 2019 | url-status=dead | access-date=18 December 2019}} {{PD-notice}} 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.{{Cite journal |date=2018-08-10 |title=FDA approves first-of-its kind targeted RNA-based therapy to treat a rare disease |url=http://dx.doi.org/10.31525/fda2-ucm616518.htm |journal=Case Medical Research |doi=10.31525/fda2-ucm616518.htm |s2cid=240302876 |issn=2643-4652|url-access=subscription }} Its mechanism-of-action is the active substance of small interfering RNA (siRNA), which allows it to interfere with and block the production of transthyretin.{{Cite journal |last1=Kristen |first1=Arnt V |last2=Ajroud-Driss |first2=Senda |last3=Conceição |first3=Isabel |last4=Gorevic |first4=Peter |last5=Kyriakides |first5=Theodoros |last6=Obici |first6=Laura |date=2019-02-01 |title=Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis |journal=Neurodegenerative Disease Management |volume=9 |issue=1 |pages=5–23 |doi=10.2217/nmt-2018-0033 |pmid=30480471 |s2cid=53756758 |issn=1758-2024|doi-access=free }} As such, it was the first FDA-approved siRNA therapeutic.

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{{cite journal |last1=Wadman |first1=Meredith | name-list-style = vanc |title=Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease|journal=Science|date=23 December 2016|url=http://www.sciencemag.org/news/2016/12/novel-drug-rescues-babies-fatal-neurodegenerative-disease|doi=10.1126/science.aal0476 |url-access=subscription}}{{Cite news|url=https://www.wsj.com/articles/surprise-drug-approval-is-holiday-gift-for-biogen-1482856447|title=Surprise Drug Approval Is Holiday Gift for Biogen|last=Grant|first=Charley | name-list-style = vanc |date=2016-12-27|newspaper=Wall Street Journal|issn=0099-9660|access-date=2016-12-27}} and soon after, from other regulatory agencies worldwide.

As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 25 in advanced clinical trials (phase II or III).{{cite journal | vauthors = Bennett CF, Swayze EE | title = RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform | journal = Annual Review of Pharmacology and Toxicology | volume = 50 | pages = 259–93 | year = 2010 | pmid = 20055705 | doi = 10.1146/annurev.pharmtox.010909.105654 }}{{cite journal | vauthors = Watts JK, Corey DR | title = Silencing disease genes in the laboratory and the clinic | journal = The Journal of Pathology | volume = 226 | issue = 2 | pages = 365–79 | date = January 2012 | pmid = 22069063 | pmc = 3916955 | doi = 10.1002/path.2993 }}

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.

Tominersen (also known as IONIS-HTT_Rx and RG6042) was tested in a phase 3 trial for Huntington's disease{{Cite journal |last1=Miller |first1=Timothy |last2=Cudkowicz |first2=Merit |last3=Shaw |first3=Pamela J. |last4=Andersen |first4=Peter M. |last5=Atassi |first5=Nazem |last6=Bucelli |first6=Robert C. |last7=Genge |first7=Angela |last8=Glass |first8=Jonathan |last9=Ladha |first9=Shafeeq |last10=Ludolph |first10=Albert L. |last11=Maragakis |first11=Nicholas J. |date=2020-07-09 |title=Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS |journal=New England Journal of Medicine |volume=383 |issue=2 |pages=109–119 |doi=10.1056/NEJMoa2003715 |issn=0028-4793 |pmid=32640130 |doi-access=free}} although this trial was discontinued on March 21, 2021, due to lack of efficacy.{{Cite news|date=2021-03-23|title=Roche drops Huntington's disease trial with once-promising drug tominersen|language=en|work=Reuters|url=https://www.reuters.com/article/us-roche-huntingtons-disease-idUSKBN2BE2W7|access-date=2021-03-25}} It is currently licensed to Roche by Ionis Pharmaceuticals.

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),{{Cite journal|last1=Langsted|first1=Anne|last2=Nordestgaard|first2=Børge G.|date=2019-05-20|title=Antisense Oligonucleotides Targeting Lipoprotein(a)|url=https://pubmed.ncbi.nlm.nih.gov/31111240/|journal=Current Atherosclerosis Reports|volume=21|issue=8|pages=30|doi=10.1007/s11883-019-0792-8|issn=1534-6242|pmid=31111240|s2cid=160014574}} 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.

Several ASOs are currently being investigated in disease models for Alexander disease,{{Cite journal|last1=Hagemann|first1=Tracy L.|last2=Powers|first2=Berit|last3=Mazur|first3=Curt|last4=Kim|first4=Aneeza|last5=Wheeler|first5=Steven|last6=Hung|first6=Gene|last7=Swayze|first7=Eric|last8=Messing|first8=Albee|date=2018|title=Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease|journal=Annals of Neurology|language=en|volume=83|issue=1|pages=27–39|doi=10.1002/ana.25118|issn=1531-8249|pmc=5876100|pmid=29226998}} ATXN2 (gene) and FUS (gene) amyotrophic lateral sclerosis, Angelman syndrome,{{Cite journal|last1=Meng|first1=Linyan|last2=Ward|first2=Amanda J.|last3=Chun|first3=Seung|last4=Bennett|first4=C. Frank|last5=Beaudet|first5=Arthur L.|last6=Rigo|first6=Frank|date=February 2015|title=Towards a therapy for Angelman syndrome by targeting a long non-coding RNA|journal=Nature|language=en|volume=518|issue=7539|pages=409–412|doi=10.1038/nature13975|pmid=25470045|issn=1476-4687|pmc=4351819|bibcode=2015Natur.518..409M}} Lafora disease, lymphoma, multiple myeloma, myotonic dystrophy, Parkinson's disease,{{Cite journal|last1=Qian|first1=Hao|last2=Kang|first2=Xinjiang|last3=Hu|first3=Jing|last4=Zhang|first4=Dongyang|last5=Liang|first5=Zhengyu|last6=Meng|first6=Fan|last7=Zhang|first7=Xuan|last8=Xue|first8=Yuanchao|last9=Maimon|first9=Roy|last10=Dowdy|first10=Steven F.|last11=Devaraj|first11=Neal K.|date=June 2020|title=Reversing a model of Parkinson's disease with in situ converted nigral neurons|url= |journal=Nature|language=en|volume=582|issue=7813|pages=550–556|doi=10.1038/s41586-020-2388-4|pmid=32581380|bibcode=2020Natur.582..550Q|s2cid=220051280|issn=1476-4687|pmc=7521455}} Pelizaeus–Merzbacher disease,{{Cite journal|last1=Elitt|first1=Matthew S.|last2=Barbar|first2=Lilianne|last3=Shick|first3=H. Elizabeth|last4=Powers|first4=Berit E.|last5=Maeno-Hikichi|first5=Yuka|last6=Madhavan|first6=Mayur|last7=Allan|first7=Kevin C.|last8=Nawash|first8=Baraa S.|last9=Gevorgyan|first9=Artur S.|last10=Hung|first10=Stevephen|last11=Nevin|first11=Zachary S.|date=2020-07-01|title=Suppression of proteolipid protein rescues Pelizaeus-Merzbacher disease|url= |journal=Nature|volume=585|issue=7825|language=en|pages=397–403|doi=10.1038/s41586-020-2494-3|pmid=32610343|s2cid=220309225|issn=1476-4687|pmc=7810164|bibcode=2020Natur.585..397E}}{{Cite web|title=Research finds new approach to treating certain neurological diseases|url=https://medicalxpress.com/news/2020-07-approach-neurological-diseases.html|access-date=2020-07-23|website=medicalxpress.com|language=en}} and prion disease,{{Cite journal|last1=Raymond|first1=Gregory J.|last2=Zhao|first2=Hien Tran|last3=Race|first3=Brent|last4=Raymond|first4=Lynne D.|last5=Williams|first5=Katie|last6=Swayze|first6=Eric E.|last7=Graffam|first7=Samantha|last8=Le|first8=Jason|last9=Caron|first9=Tyler|last10=Stathopoulos|first10=Jacquelyn|last11=O'Keefe|first11=Rhonda|date=2019-08-22|title=Antisense oligonucleotides extend survival of prion-infected mice|journal=JCI Insight|language=en|volume=4|issue=16|doi=10.1172/jci.insight.131175|pmid=31361599|pmc=6777807|issn=0021-9738|doi-access=free}} Rett syndrome,{{Cite journal|last1=Sztainberg|first1=Yehezkel|last2=Chen|first2=Hong-mei|last3=Swann|first3=John W.|last4=Hao|first4=Shuang|last5=Tang|first5=Bin|last6=Wu|first6=Zhenyu|last7=Tang|first7=Jianrong|last8=Wan|first8=Ying-Wooi|last9=Liu|first9=Zhandong|last10=Rigo|first10=Frank|last11=Zoghbi|first11=Huda Y.|date=December 2015|title=Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides|journal=Nature|language=en|volume=528|issue=7580|pages=123–126|doi=10.1038/nature16159|pmid=26605526|issn=1476-4687|pmc=4839300|bibcode=2015Natur.528..123S}} spinocerebellar Ataxia Type 3.

• Antisense
• Antisense mRNA
• Locked nucleic acid
• Morpholino
• Oligonucleotide synthesis
• Peptide nucleic acid
• RNA interference (which uses double-strand RNA)

{{reflist}}

• [http://www.medicalnewstoday.com/medicalnews.php?newsid=74957 Antisense Pharma: Promising Phase IIb Results Of Targeted Therapy With AP 12009 In Recurrent Anaplastic Astrocytoma]

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