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.