Antisense Oligonucleotide Drugs

Applications

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Antisense Oligonucleotide Drugs

Antisense oligonucleotide (ASO) is a single-stranded DNA/RNA (15-25 nt) designed to bind complementary mRNA target, ultimately facilitating its degradation. ASO drugs bear great therapeutic potential toward treatment of various diseases by altering RNA and/or reducing, restoring, and modifying protein expression through multiple molecular mechanisms. As of now, six ASO drugs have been approved by FDA to treat various diseases such as CMV retinitis, familial hypercholesterolemia, veno-occlusive disease, Duchenne muscular dystrophy, spinal muscular atrophy and familial amyloid polyneuropathy.

The goal of the ASO drugs is the downregulation of molecular target. The two most widely-used ASOs are double-stranded ASO and single-stranded ASO. The former uses the RISC complex to degrade RNA, while the latter silences gene expression by a variety of mechanisms, including the following:

  • Inhibiting 5'cap formation
  • Steric blocking of protein translation
  • Inhibiting or altering RNA splicing
  • Activation of RNase H, which degrades the target mRNA

Single-stranded ASO mechanism of action.Fig1. Single-stranded ASO mechanism of action.

Currently, ASOs drugs have been extensively chemically modified to increase stability, affinity, specificity and delivery while decreasing the potential for off-target effects. The chemical modifications of ASOs are generally classified as first generation, second generation, and third generation.

ASO modifications

  • First generation modifications include changes made to the phosphodiester backbone, heterocyclic nucleobase and sugar moiety to increase affinity and specificity of the ASO.
  • Second generation modifications that modify the sugar moiety of the nucleobase (pyrimidine, purine) thereby increasing binding affinity to the target RNA and solving the problems of low specificity/cellular uptake.
  • Third generation ASOs carry modifications to the furanose ring of the nucleotide4. They bind with greater affinity and specificity to target DNA or RNA than unmodified oligonucleotides, and reduce protein expression by sterically inhibiting the translation machinery.

IntegrateRNA has many years of experience in RNA research, providing professional and high quality services and products for RNA basic research, drug discovery and clinical research. We provide ASO synthesis, in vitro screening and in vivo testing services. We guarantee strict quality control and deliver your RNA services/products in the most efficient time to meet your needs. If you have any question, please feel free to contact us.

References:

  1. Aboul-Fadl T. et al. Antisense oligonucleotide technologies in drug discovery. Expert Opinion on Drug Discovery, 2006, 1(4):285-8.
  2. Chery J. et al. RNA therapeutics: RNAi and antisense mechanisms and clinical applications. Postdoc Journal, 2016, 4(7).
For research use only. Not intended for any clinical use.
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