Antisense oligonucleotides

1. TOPIC: ANTISENSE OLIGONUCLEOTIDE
PRESENTED BY:
Omkar Kumar Kuwar
Department of Pharmacology
ISF College of Pharmacy, MOGA
omkar.official.955@gmail.com
GUIDED BY:
Dr. Arti Singh
Associate Professor
Department of Pharmacology
ISF College of Pharmacy, MOGA
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2. CONTENTS
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ISF college of pharmacy
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 Introduction
 Definition
 Mechanism of ASO action
 Advantages
 Challenges & Limitations
 Applications
 Refrences

3. INTRODUCTION to antisense oliGonucleotide
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Refrencs; https://link.springer.com/article/10.1007/s40259-024-00644-7
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 Antisense : complementary or negative base sequence to a portion of the
coding or positive sense mRNA.
 Oligo : means scant or few
 Nucleotide : 5 organic molecule that make up the backbone of the DNA &
RNA. ( ATCGU)
 Antisense oligonucleotide therapy is a new way to block protein function is to
prevent the translation of protein by inhibiting translation step.
 Antisense oligonucleotides (ASOs) are synthetic single stranded
oligonucleotides that can bind to precursor mRNA (pre-mRNA) and/or
mRNA through Watson-Crick base pairing.
 ASOs can modulate the function of RNA, there by regulating gene expression.

4. definition
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Refrencs; https://link.springer.com/article/10.1007/s40259-024-00644-7
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 Oligonucleotides are chemically synthesized using phosphoramides.
 The oligonucleotide chain proceeds in direction of 3’ to 5’ terminus.
 Antisense RNA prevent protein translation of certain mRNA strands by
binding to them.
 Antisense DNA can be used to target a specific cRNA.

5. Mechanismsof ASOs Action
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Refrence; www.researchgate.net
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6. Mechanismsof ASOs Action
2/27/2024
Refrence; www.researchgate.net
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7. Fomivirsensodium
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Refrence ; Drug bank
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 Fomivirsen is a 21-base phosphorothioate oligonucleotide.
 Fomivirsen is marketed under the trade name Vitravene for
intravitreal injection and was the first antisense drug to be
approved by the Food and Drug Administration (FDA).
 Indication
Indicated for the local treatment of cytomegalovirus (CMV)
retinitis in patients with acquired immunodeficiency syndrome
(AIDS),
• injected into the eye (intravitreal) 330 µg ( 0.05 mL/eye )
 Half-life about 55-78 hours.
CMV is a viral infection of the retina of the eye resulting if the
eye inflammation.

8. Mipomersen
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Refrence ; Drug bank
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 Familial hypercholesterolemia is a genetic disorder caused by a
defect on chromosome-19, that makes the body unable to remove
LDL. Or bad cholesterol this results in high level of LDL in blood.
 The FDA label includes a black box warning of hepatoxicity.
 Administer through subcutanious 200 mg/1mL
 Half-life: 1-2 months.
 Drug interaction:
Acetaminophen, Amiodarone, Demeclocycline, Doxycycline,
Eravacycline,
They may increase the hepatotoxic activities of Mipomersen.
 Food Interactions;
Avoid excessive or chronic alcohol consumption. Alcohol may increase
the risk of liver injury.

9. Eteplirsen
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Refrence ; Drug bank
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 Used to treat Duchenne muscular dystrophy (DMD)
 Duchenne muscular dystrophy is a rare genetic disorder
characterized by progressive muscle deterioration and premature
death most commonly due to respiratory or cardiac complications.
 It is caused by loss-of-function mutations in the DMD gene coding
for dystrophin, an essential protein involved in maintaining the
structural integrity and function of muscle fibres.
 Approved by the FDA in September 2016.
 Administer Intravenous strength 50 mg/mL
 Half-life (t1/2) 3-4 h.

10. Nusinersen
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Refrence ; Drug bank
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 Spinal muscular atrophy. It is a disorder affecting the motor
neurons-nerves that control voluntary muscle movement.
 It is administrated as direct 2.4 mg/1mL Intrathecal.
 Half-life: 135 to 177 days in CSF, and 63 to 87 days in plasma.
 Toxicity ; Acute neurological impairment.

11. Inotersen
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Refrence ; Drug bank
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 Used in the treatment of polyneuropathy caused by
hereditary transthyretin-mediated amyloidosis in
adults.
 It was FDA approved in October 2018.
 Dose 284 mg Subcutaneous.
 Food Interactions; Adm. of vitamin A supplement.

12. ADVANTAGES
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Refrencs; https://link.springer.com/article/10.1007/s40259-024-00644-7
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 Oligonucleotides are manufactured quickly (within a week).
 Sensitivity of therapy can be easily measured.
 Potential to produce longer lasting responses.
 Potential for enhanced binding affinity to target.

13. Challenges and LIMITATIONS
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Refrencs; https://link.springer.com/article/10.1007/s40259-024-00644-7
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 Off-Target Effects
 Unintended binding to non-target RNA sequences can lead to adverse effects or reduced
specificity.
 Delivery Efficiency
 Ensuring effective uptake and distribution of oligonucleotides to target tissues while minimizing
off-target accumulation.

14. APPLICATIONS
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Refrencs; https://link.springer.com/article/10.1007/s40259-024-00644-7
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 Inflammation therapeutics [Duchenne muscular dystrophy] (eteplirsen, golodirsen,
viltolarsen, and casimersen)
 CVS [Homozygous familial hypercholesterolemia] (mipomersen),
 Antiviral [Cytomegalovirus retinitis] (fomivirsen),
 Spinal muscular atrophy (nusinersen).
 Hereditary transthyretin amyloidosis (inotersen) and amyotrophic lateral sclerosis (tofersen).

15. References
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ISF college of pharmacy
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 Chan JHP, Lim S, Wong WSF. Antisense oligonucleotides: from design to therapeutic
application. Clin Exp Pharmacol Physiol. 2006;33:533–40.
 Crooke ST, Baker BF, Crooke RM, Liang XH. Antisense technology: an overview and prospectus.
Nat Rev Drug Discov. 2021;20:427–53.
 Alama A, Barbieri F, Cagnoli M, Schettini G. Antisense oligonucleotides as therapeutic agents.
Pharmacol Res. 1997;36:171–8.
 https://www.researchgate.net/publication/377597137_Splice-
Modulating_Antisense_Oligonucleotides_as_Therapeutics_for_Inherited_Metabolic_Diseases
 https://link.springer.com/article/10.1007/s40259-024-00644-7

16. 2/27/2024
ISF college of pharmacy