Antisense Oligonucleotides

• The monomers are chemically-modified deoxynucleotides like those in DNA or ribonucleotides like those in RNA.
• There are usually only 15–30 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.

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 ASO ("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

  The U. S. FDA has approved fomivirsen (Vitravene®) for use against HCMV infections of the eye in AIDS patients. Fomivirsen is an antisense oligonucleotide (ASO) that degrades the mRNA of essential viral proteins. (For economic reasons, this drug is no longer available.)

• 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 [Link]. On 31 January 2013, the ASO mipomersen (Kynamro®) received regulatory approval for use in humans with familial hypercholesterolemia.
• spinal muscular atrophy (SMA). In this inherited disorder, babies are homozygous for a mutant gene, SMN1, whose protein product is essential for survival of motor neurons controlling muscle contraction. A related gene, SMN2, produces small amounts of a similar protein that can provide some compensation. but it does not function well because an essential exon is spliced out during the processing of its mRNA. However, an ASO called nusinersen (Spinraza®) enables that exon to be retained in the mRNA and a functioning protein is made. When injected into the cerebrospinal fluid (CSF) of infants and children suffering from SMA, the results have been so promising that on December 23, 2016, the U. S. FDA approved its use.
• Huntington's disease. (In March 2021, three trials of ASOs targeting the mutant protein in Huntington's disease were halted because the drugs showed no benefit.)
• hereditary angioedema (HAE). An ASO (donidalorsen®), showing promise in clinical trials, destroys the mRNA encoding prekallikrein, the precursor leading to the formation of the potent inflammatory bradykinin.