11.11: Antisense Oligodeoxynucleotides and their Therapeutic Potential
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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.
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.
To be useful in human therapy, antisense oligonucleotides must be able to enter the target cells; avoid digestion by nucleases; and not cause dangerous side-effects. To achieve these goals, antisense oligonucleotides are generally chemically modified to resist digestion by nucleases and attached to a targeting device such as the ligand for the type of receptors found on desired target cells or 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.