Antisense Oligonucleotides

• 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.

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.

• 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.

Several laboratories are presently testing antisense oligonucleotides as weapons against:

• HIV-1, the most frequent cause of AIDS in the United States
• human cytomegalovirus (HCMV); which frequently causes serious complications in AIDS patients

  The U. S. FDA has approved fomivirsen (Vitravene®) for use against HCMV infections of the eye in AIDS patients. Fomivirsen is an antisense oligodeoxynucleotide (ODN) that degrades the mRNA of essential viral proteins.

• asthma; inhalation of an antisense oligonucleotide reduces (at least in rabbits) the synthesis of cell receptors involved in 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 [Link]