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11.10: Antisense Oligodeoxynucleotides and their Therapeutic Potential

Antisense oligonucleotides are synthetic polymers:

  • The monomers are chemically-modified deoxynucleotides like those in DNA or ribonucleotides like those in RNA.
  • There are usually only 15–20 of them, hence "oligo".
  • Their sequence (3′ → 5′) is antisense; that is, complementary to the sense sequence of a molecule of mRNA.

Fig. 11.10.1 Antisense oligonucleotides

Antisense oligonucleotides are synthesized in the hope that they can be used as therapeutic agents — blocking disease processes by altering the synthesis of a particular protein. This would be achieved by the binding of the antisense oligonucleotide to the mRNA from which that protein is normally synthesized. Binding of the two may

  • physically block the ability of ribosomes to move along the messenger RNA preventing synthesis of the protein;
  • hasten the rate at which the mRNA is degraded within the cytosol;
  • prevent splicing errors that would otherwise produce a defective protein.

In order to be useful in human therapy, antisense oligonucleotides must

  • be able to enter the target cells;
  • avoid digestion by nucleases;
  • not cause dangerous side-effects.

To achieve these goals, antisense oligonucleotides are generally

  • chemically modified to resist digestion by nucleases;
  • attached to a targeting device such as
    • the ligand for the type of receptors found on desired target cells;
    • antibodies directed against molecules on the surface of the desired target cells.

Antisense Oligonucleotides Uses

A variety of antisense oligonucleotides are being tested as possible weapons against:

  • Hepatitis C virus (HCV). Successful infection of the liver by this virus requires that the liver produce a particular microRNA (miRNA-122). Injections of HCV-infected humans with an ODN ("miravirsen") complementary to miRNA-122 suppresses the virus.
  • HIV-1, the most frequent cause of AIDS in the United States
  • Ebola virus, the cause of the often-fatal Ebola hemorrhagic fever
  • human cytomegalovirus (HCMV); which frequently causes serious complications in AIDS patients
  • asthma; inhalation of an antisense oligonucleotide targeting the mRNA of GATA3 (a transcription factor that promotes Th2 responses) provides relief to patients with allergic asthma.
  • certain cancers, e.g., chronic myelogenous leukemia (CML)
  • certain types of inflammation caused by cell-mediated immune reactions
  • Duchenne muscular dystrophy (DMD)
  • familial hypercholesterolemia — targets the mRNA for apolipoprotein B-100. On 31 January 2013, the antisense ODN mipomersen (Kynamro®) received regulatory approval for use in humans with familial hypercholesterolemia.