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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 blockade, and exon content modulation through splicing site binding on pre-mRNA.^[1]

Approved therapies

ASO-based drugs employ highly modified, synthetic nucleic acids which achieve wide tissue distribution with very long half-lives.^[2]^[3]^[4] Several ASOs have been approved in the United States, European Union, and elsewhere.

Batten disease

Milasen was 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.^[5]^[6]

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).^[5] 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.^[5] However it is an example of individualized genomic medicine therapeutical intervention.^[5]^[7]

Cytomegalovirus retinitis

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

Duchenne muscular dystrophy

Several morpholino oligos have been approved to treat specific groups of mutations causing Duchenne muscular dystrophy. In September 2016 eteplirsen (ExonDys51) received FDA approval^[8] 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^[9] for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript.

Familial chylomicronaemia syndrome

Volanesorsen was approved by the European Medicines Agency (EMA) for treatment of familial chylomicronaemia syndrome in May 2019.^[10]

Familial hypercholesterolemia

In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia.^[11]^[12]

Hereditary transthyretin-mediated amyloidosis

Inotersen received FDA approval for the treatment of hereditary transthyretin-mediated amyloidosis in October 2018.^[13] The application for inotersen was granted orphan drug designation.^[13] It was developed by Ionis Pharmaceuticals and licensed to Akcea Therapeutics.

Spinal muscular atrophy

In 2004, development of an antisense therapy for spinal muscular atrophy began. Over the following years, an antisense oligonucleotide later named nusinersen was developed byIonis Pharmaceuticals under under a licensing agreement with Biogen. In December 2016, nusinersen received regulatory approval from FDA^[14]^[15] and soon after, from other regulatory agencies worldwide.

Investigational therapies

Current clinical trials

As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 25 in advanced clinical trials (phase II or III).^[16]^[17]

Phase III trials

Amyotrophic lateral sclerosis

Tofersen (also known as IONIS-SOD1_{Rx and} BIIB067) is currently being tested in a phase 3 trial for amyotrophic lateral sclerosis (ALS) due to mutations in the SOD1 gene.^[18] Results from a phase 1/2 trial have been promising.^[19] It is being developed by Biogen under a licensing agreement with Ionis Pharmaceuticals.

Hereditary transthyretin-mediated amyloidosis

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

Tominersen (also known as IONIS-HTT_Rx and RG6042) is currently being tested in a phase 3 trial for Huntington's disease.^[19] It is being developed by Roche under a licensing agreement with Ionis Pharmaceuticals.

Phase I & II trials

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, 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

Several ASOs are currently being investigated in disease models for Alexander disease,^[20] ATXN2 (gene) and FUS (gene) amyotrophic lateral sclerosis, Angelman syndrome,^[21] Lafora disease, lymphoma, multiple myeloma, myotonic dystrophy, Parkinson's disease,^[22] Pelizaeus–Merzbacher disease,^[23]^[24] and prion disease,^[25] Rett syndrome,^[26] spinocerebellar Ataxia Type 3.

Nomenclature

The common stem for antisense oligonucleotides is -rsen. The substem -virsen designates antiviral antisense oligonucleotides.^[27]

Pharmacokinetics and pharmacodynamics

Half-life and stability

Because nucleases that cleave the phosphodiester linkage in DNA are expressed in almost every cell, unmodified DNA molecules are generally degraded before they reach their targets. Therefore, antisense drug candidate molecules are generally modified during the drug discovery phase of their development.^[28]^[29] Additionally, most targets of antisense are located inside cells, and getting nucleic acids across cell membranes is also difficult. Therefore, most clinical candidates have modified DNA "backbones", or the nucleobase or sugar moieties of the nucleotides are altered.

In vivo delivery

ASOs can 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.

Delivery efficiency and cell-type specific targeting is greatly enhanced with the use of conjugated ligands.^[30]

References

^ 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.
^ Weiss, B. (ed.): Antisense Oligodeoxynucleotides and Antisense RNA : Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997. ISBN 0849385520 ISBN 9780849385520
^ 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.
^ Goodchild J (2011). "Therapeutic oligonucleotides". Methods in Molecular Biology. 764: 1–15. doi:10.1007/978-1-61779-188-8_1. ISBN 978-1-61779-187-1. PMID 21748630.
^ ^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. 0 (17): 1644–1652. doi:10.1056/NEJMoa1813279. ISSN 0028-4793. PMC 6961983. PMID 31597037.
^ Gallagher, James (2019-10-12). "Unique drug for a girl with deadly brain disease". Retrieved 2019-10-14.
^ "A Drug Was Made For Just One Child, Raising Hopes About Future Of Tailored Medicine". www.wbur.org. Retrieved 2019-10-14.
^ 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
^ U.S. Food and Drug Administration, Silver Springs, Maryland. News Release: FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation, December 12, 2019. Archived December 13, 2019, at the Wayback Machine
^ https://www.globenewswire.com/news-release/2019/05/07/1818393/0/en/Akcea-and-Ionis-Announce-Approval-of-WAYLIVRA-volanesorsen-in-the-European-Union.html
^ Pollack, Andrew (29 January 2013). "F.D.A. Approves Genetic Drug to Treat Rare Disease". The New York Times. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
^ "FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder". U.S. Food and Drug Administration. 29 January 2013. {{cite web}}: Cite uses deprecated parameter |authors= (help)
^ ^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. This article incorporates text from this source, which is in the public domain.
^ Wadman, Meredith (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science. doi:10.1126/science.aal0476. {{cite journal}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
^ Grant, Charley (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
^ 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.
^ 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.
^ Miller, Timothy M.; Pestronk, Alan; David, William; Rothstein, Jeffrey; Simpson, Ericka; Appel, Stanley H.; Andres, Patricia L.; Mahoney, Katy; Allred, Peggy; Alexander, Katie; Ostrow, Lyle W. (2013-05-01). "An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study". The Lancet Neurology. 12 (5): 435–442. doi:10.1016/S1474-4422(13)70061-9. ISSN 1474-4422. PMID 23541756.
^ ^a ^b 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.
^ 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.
^ 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. doi:10.1038/nature13975. ISSN 1476-4687.
^ 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. doi:10.1038/s41586-020-2388-4. ISSN 1476-4687.
^ 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: 1–9. doi:10.1038/s41586-020-2494-3. ISSN 1476-4687.
^ "Research finds new approach to treating certain neurological diseases". medicalxpress.com. Retrieved 2020-07-23.
^ 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.
^ 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. (2015-12). "Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides". Nature. 528 (7580): 123–126. doi:10.1038/nature16159. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)
^ International Nonproprietary Names (INN) for biological and biotechnological substances
^ 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.
^ 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.
^ 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.

External links

Antisense Pharma: Promising Phase IIb Results Of Targeted Therapy With AP 12009 In Recurrent Anaplastic Astrocytoma

[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] Weiss, B. (ed.): Antisense Oligodeoxynucleotides and Antisense RNA : Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997. ISBN 0849385520 ISBN 9780849385520

[pmid102285542-3] 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.

[4] Goodchild J (2011). "Therapeutic oligonucleotides". Methods in Molecular Biology. 764: 1–15. doi:10.1007/978-1-61779-188-8_1. ISBN 978-1-61779-187-1. PMID 21748630.

[:02-5] 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. 0 (17): 1644–1652. doi:10.1056/NEJMoa1813279. ISSN 0028-4793. PMC 6961983. PMID 31597037.

[6] Gallagher, James (2019-10-12). "Unique drug for a girl with deadly brain disease". Retrieved 2019-10-14.

[7] "A Drug Was Made For Just One Child, Raising Hopes About Future Of Tailored Medicine". www.wbur.org. Retrieved 2019-10-14.

[8] 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

[9] U.S. Food and Drug Administration, Silver Springs, Maryland. News Release: FDA grants accelerated approval to first targeted treatment for rare Duchenne muscular dystrophy mutation, December 12, 2019. Archived December 13, 2019, at the Wayback Machine

[10] ttps://www.globenewswire.com/news-release/2019/05/07/1818393/0/en/Akcea-and-Ionis-Announce-Approval-of-WAYLIVRA-volanesorsen-in-the-European-Union.html

[11] Pollack, Andrew (29 January 2013). "F.D.A. Approves Genetic Drug to Treat Rare Disease". The New York Times. {{cite web}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)

[12] "FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder". U.S. Food and Drug Administration. 29 January 2013. {{cite web}}: Cite uses deprecated parameter |authors= (help)

[FDA_Snapshot-13] "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. This article incorporates text from this source, which is in the public domain.

[14] Wadman, Meredith (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science. doi:10.1126/science.aal0476. {{cite journal}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)

[15] Grant, Charley (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)

[16] 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.

[17] 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.

[18] Miller, Timothy M.; Pestronk, Alan; David, William; Rothstein, Jeffrey; Simpson, Ericka; Appel, Stanley H.; Andres, Patricia L.; Mahoney, Katy; Allred, Peggy; Alexander, Katie; Ostrow, Lyle W. (2013-05-01). "An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study". The Lancet Neurology. 12 (5): 435–442. doi:10.1016/S1474-4422(13)70061-9. ISSN 1474-4422. PMID 23541756.

[Miller_109–119-19] 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.

[20] 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.

[21] 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. doi:10.1038/nature13975. ISSN 1476-4687.

[22] 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. doi:10.1038/s41586-020-2388-4. ISSN 1476-4687.

[23] 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: 1–9. doi:10.1038/s41586-020-2494-3. ISSN 1476-4687.

[24] "Research finds new approach to treating certain neurological diseases". medicalxpress.com. Retrieved 2020-07-23.

[25] 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.

[26] 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. (2015-12). "Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides". Nature. 528 (7580): 123–126. doi:10.1038/nature16159. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)

[WHO2010-27] International Nonproprietary Names (INN) for biological and biotechnological substances

[Bennett-28] 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.

[pmid20575003-29] 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.

[Bennett22-30] 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.

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@@ Line 32: / Line 32: @@
 === Current clinical trials ===
-As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 20 in [[Clinical trial phase|advanced clinical trials]] (phase II or III).<ref>{{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 }}</ref><ref>{{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 }}</ref>
+As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 25 in [[Clinical trial phase|advanced clinical trials]] (phase II or III).<ref>{{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 }}</ref><ref>{{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 }}</ref>
-==== Amyotrophic lateral sclerosis ====
+==== Phase III trials ====
+===== Amyotrophic lateral sclerosis =====
 Tofersen (also known as IONIS-SOD1<sub>Rx and</sub> BIIB067) is currently being tested in a phase 3 trial for [[amyotrophic lateral sclerosis]] (ALS) due to mutations in the [[SOD1]] gene.<ref>{{Cite journal|last=Miller|first=Timothy M.|last2=Pestronk|first2=Alan|last3=David|first3=William|last4=Rothstein|first4=Jeffrey|last5=Simpson|first5=Ericka|last6=Appel|first6=Stanley H.|last7=Andres|first7=Patricia L.|last8=Mahoney|first8=Katy|last9=Allred|first9=Peggy|last10=Alexander|first10=Katie|last11=Ostrow|first11=Lyle W.|date=2013-05-01|title=An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study|url=https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(13)70061-9/abstract|journal=The Lancet Neurology|language=English|volume=12|issue=5|pages=435–442|doi=10.1016/S1474-4422(13)70061-9|issn=1474-4422|pmid=23541756}}</ref> Results from a phase 1/2 trial have been promising.<ref name="Miller 109–119">{{Cite journal|last=Miller|first=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|url=https://doi.org/10.1056/NEJMoa2003715|journal=New England Journal of Medicine|volume=383|issue=2|pages=109–119|doi=10.1056/NEJMoa2003715|issn=0028-4793}}</ref> It is being developed by Biogen under a licensing agreement with Ionis Pharmaceuticals.
-==== Hereditary transthyretin-mediated amyloidosis ====
+===== Hereditary transthyretin-mediated amyloidosis =====
 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 ====
+===== Huntington's disease =====
-Tominersen (also known as IONIS-HTT<sub>Rx</sub> and RG6042) is currently being tested in a phase 3 trial for [[Huntington's disease]].<ref name="Miller 109–119"/> It is being developed by [[Hoffmann-La Roche|Roche]] under a licensing agreement with Ionis Pharmaceuticals.
+Tominersen (also known as IONIS-HTT<sub>Rx</sub> and RG6042) is currently being tested in a phase 3 trial for [[Huntington's disease]].<ref name="Miller 109–119" /> It is being developed by [[Hoffmann-La Roche|Roche]] under a licensing agreement with Ionis Pharmaceuticals.
+==== Phase I & II trials ====
+Clinical trials are ongoing for several diseases and conditions including:
+[[Acromegaly]], [[Age related macular degenartion|age related macular degeneration]], [[Alzheimer's disease]], [[amyotrophic lateral sclerosis]], [[Retinitis pigmentosa|autosomal dominant retinitis pigmentosa]], [[beta thalassemia]], [[cardiovascular disease]], [[centronuclear myopathy]], [[Coagulopathy|coagulopathies]], [[cystic fibrosis]], [[Duchenne muscular dystrophy]], [[diabetes]], [[epidermolysis bullosa dystrophica]], [[Familial Chylomicronemia Syndrome|familial chylomicronemia syndrome]], [[frontotemporal dementia]], [[Fuchs' dystrophy]], [[hepatitis B]], [[Hereditary angioedema|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|STAT3-expressing]] [[Cancer|cancers]], [[Usher syndrome]].
 === Preclinical development ===
-Several ASOs are currently being investigated in disease models for [[Alexander disease]],<ref>{{Cite journal|last=Hagemann|first=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|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25118|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}}</ref> [[ATXN2|ATXN2 (gene)]] and [[FUS (gene)]] [[amyotrophic lateral sclerosis]], [[Angelman syndrome]],<ref>{{Cite journal|last=Meng|first=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|url=https://www.nature.com/articles/nature13975|journal=Nature|language=en|volume=518|issue=7539|pages=409–412|doi=10.1038/nature13975|issn=1476-4687}}</ref> [[Lafora disease]], [[lymphoma]], [[multiple myeloma]], [[Parkinson's disease]],<ref>{{Cite journal|last=Qian|first=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=https://www.nature.com/articles/s41586-020-2388-4|journal=Nature|language=en|volume=582|issue=7813|pages=550–556|doi=10.1038/s41586-020-2388-4|issn=1476-4687}}</ref> [[Pelizaeus–Merzbacher disease]],<ref>{{Cite journal|last=Elitt|first=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=https://www.nature.com/articles/s41586-020-2494-3|journal=Nature|language=en|pages=1–9|doi=10.1038/s41586-020-2494-3|issn=1476-4687}}</ref> and [[prion disease]].<ref>{{Cite journal|last=Raymond|first=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|url=https://insight.jci.org/articles/view/131175|journal=JCI Insight|language=en|volume=4|issue=16|doi=10.1172/jci.insight.131175|issn=0021-9738}}</ref>
+Several ASOs are currently being investigated in disease models for [[Alexander disease]],<ref>{{Cite journal|last=Hagemann|first=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|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25118|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}}</ref> [[ATXN2|ATXN2 (gene)]] and [[FUS (gene)]] [[amyotrophic lateral sclerosis]], [[Angelman syndrome]],<ref>{{Cite journal|last=Meng|first=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|url=https://www.nature.com/articles/nature13975|journal=Nature|language=en|volume=518|issue=7539|pages=409–412|doi=10.1038/nature13975|issn=1476-4687}}</ref> [[Lafora disease]], [[lymphoma]], [[multiple myeloma]], [[myotonic dystrophy]], [[Parkinson's disease]],<ref>{{Cite journal|last=Qian|first=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=https://www.nature.com/articles/s41586-020-2388-4|journal=Nature|language=en|volume=582|issue=7813|pages=550–556|doi=10.1038/s41586-020-2388-4|issn=1476-4687}}</ref> [[Pelizaeus–Merzbacher disease]],<ref>{{Cite journal|last=Elitt|first=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=https://www.nature.com/articles/s41586-020-2494-3|journal=Nature|language=en|pages=1–9|doi=10.1038/s41586-020-2494-3|issn=1476-4687}}</ref><ref>{{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}}</ref> and [[prion disease]],<ref>{{Cite journal|last=Raymond|first=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|url=https://insight.jci.org/articles/view/131175|journal=JCI Insight|language=en|volume=4|issue=16|doi=10.1172/jci.insight.131175|issn=0021-9738}}</ref> [[Rett syndrome]],<ref>{{Cite journal|last=Sztainberg|first=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=2015-12|title=Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides|url=https://www.nature.com/articles/nature16159|journal=Nature|language=en|volume=528|issue=7580|pages=123–126|doi=10.1038/nature16159|issn=1476-4687}}</ref> [[Spinocerebellar Ataxia Type-3|spinocerebellar Ataxia Type 3]].
 ==Nomenclature==

Revision as of 09:45, 23 July 2020

Approved therapies

Batten disease

Cytomegalovirus retinitis

Duchenne muscular dystrophy

Familial chylomicronaemia syndrome

Familial hypercholesterolemia

Hereditary transthyretin-mediated amyloidosis

Spinal muscular atrophy

Investigational therapies

Current clinical trials

Phase III trials

Amyotrophic lateral sclerosis

Hereditary transthyretin-mediated amyloidosis

Huntington's disease

Phase I & II trials

Preclinical development

Nomenclature

Pharmacokinetics and pharmacodynamics

Half-life and stability

In vivo delivery

See also

References

External links