Antisense therapy

Antisense therapy is a form of treatment for genetic disorders or infections. When the sequence of a gene is known to cause a particular disease, it is possible to synthesize a strand of nucleic acid that will bind to the messenger RNA (mRNA) produced by that gene and inactivate it, effectively turning that gene "off". This is because mRNA has to be single stranded for it to be translated. Alternatively, the strand might be targeted to bind a splicing site on pre-mRNA and modify the exon content of an mRNA.[1] Antisense therapies are not gene therapies, and should be considered RNA-based drug discovery, as it has only a few elements in common with gene therapy.[2]

This synthesized nucleic acid is termed an "antisense" oligonucleotide (ASO) because its base sequence is complementary to the gene's messenger RNA (mRNA), which is called the "sense" sequence (so that a sense segment of mRNA " 5'-AAGGUC-3' " would be blocked by the antisense mRNA segment " 3'-UUCCAG-5' ").

Antisense oligonucleotides have been researched as potential drugs[3][4][5] for diseases such as cancers (including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes, amyotrophic lateral sclerosis (ALS), Parkinson's disease,[6] Duchenne muscular dystrophy, spinal muscular atrophy, Ataxia–telangiectasia (in vitro) and diseases such as asthma, arthritis and pouchitis with an inflammatory component. As of 2016, several antisense drugs have been approved in the US, European Union and elsewhere: fomivirsen as a treatment for cytomegalovirus retinitis, mipomersen for homozygous familial hypercholesterolemia, eteplirsen for Duchenne muscular dystrophy, and nusinersen for spinal muscular atrophy.

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).[7] 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.[7] However it is an example of individualized genomic medicine therapeutical intervention.[7][8]

Example antisense therapies

As of 2012, some 40 antisense oligonucleotides and siRNAs were in clinical trials, including over 20 in advanced clinical trials (phase II or III).[9][10]

Batten disease

Milasen was a novel individualized therapeutic agent that was designed and approved by the FDA for the treatment of Batten disease in the eponymous patient, Mila Makovec. This therapy serves as an example of personalized medicine.[7][11]

Cytomegalovirus retinitis

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

Familial hypercholesterolemia

In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia.[12][13]

Spinal muscular atrophy

In 2004, development of an antisense therapy for spinal muscular atrophy was started. 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.[14][15]

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[16] 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[17] for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript.

Nomenclature

The common stem for antisense oligonucleotides is -rsen. The substem -virsen designates antiviral antisense oligonucleotides.[18]

Delivery

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.[19][20] 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. Additionally, other molecules may be conjugated to antisense molecules in order to improve their ability to target certain cells or to cross barriers like cell membranes or the blood brain barrier.[19]

See also

References
  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. Crooke, Stanley T. (2002). "Antisense: Progress toward Gene-Directed Cancer Therapy". Encyclopedia of Cancer. pp. 127–134. doi:10.1016/B0-12-227555-1/00013-7. ISBN 9780122275555.
  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.
  5. 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.
  6. Uehara T, Choong CJ, Nakamori M, Hayakawa H, Nishiyama K, Kasahara Y, et al. (May 2019). "Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting α-synuclein as a novel therapy for Parkinson's disease". Scientific Reports. 9 (1): 7567. doi:10.1038/s41598-019-43772-9. PMC 6527855. PMID 31110191.
  7. 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.
  8. "A Drug Was Made For Just One Child, Raising Hopes About Future Of Tailored Medicine". www.wbur.org. Retrieved 2019-10-14.
  9. 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.
  10. 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.
  11. Gallagher, James (2019-10-12). "Unique drug for a girl with deadly brain disease". Retrieved 2019-10-14.
  12. Pollack A (29 January 2013). "F.D.A. Approves Genetic Drug to Treat Rare Disease". The New York Times.
  13. Staff (29 January 2013). "FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder". U.S. Food and Drug Administration.CS1 maint: uses authors parameter (link)
  14. Wadman M (23 December 2016). "Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease". Science. doi:10.1126/science.aal0476.
  15. Grant C (2016-12-27). "Surprise Drug Approval Is Holiday Gift for Biogen". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-12-27.
  16. 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[Date mismatch], at the Wayback Machine
  17. 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
  18. International Nonproprietary Names (INN) for biological and biotechnological substances
  19. 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.
  20. 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.
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