Biomedical Engineering Reference
In-Depth Information
14.7.2 Uses, advantages and disadvantages of 'oligos'
Antisense oligonucleotides (oligos) are being assessed in preclinical and clinical studies as therapeu-
tic agents in the treatment of cancer, as well as a variety of viral diseases (e.g. HIV, hepatitis B, herpes
and papillomavirus infections). They also have potential application in treating other disease states
for which blocking of gene expression would likely have a benefi cial effect. Such medical conditions
include restenosis, rheumatoid arthritis and allergic disorders. Cancer, however, remains the most
common target indication. The favoured approach is to target genes whose expression/up-regulation
triggers or fuels tumorigenesis. These include products of the BCL-2, survivin and clusterin genes.
The BCL-2 oncogene products drive neoplastic progression by enhancing cell survival via inhibition
of apoptosis. Survivin is generally not expressed in healthy tissue, but expressed at high levels in a
range of common cancer types, including lung, colon, breast and prostate cancers. It plays an im-
portant role in both promoting cell division and inhibiting apoptosis. The clusterin gene codes for a
cytoprotective 'chaperone' protein whose up-regulation is associated with various human cancers.
As potential drugs, antisense oligos display a number of desirable characteristics, the most
signifi cant of which is their likely specifi city. Statistical analysis reveals that any specifi c base
sequence of 17 or more bases is extremely unlikely to occur more than once in a human cell's
nucleic acid complement. It thus follows that an oligonucleotide of 17 or more nucleotide units in
length, which is designed to duplex successfully with a specifi c mRNA species, is unlikely to form
a duplex with any other (unintended) mRNA species. Most synthetic oligos, therefore, are in the
region of 17 nucleotide units long. These will display virtually an absolute specifi city for the target
sequence. Additional advantages of the oligonucleotide antisense approach include:
Relatively low toxicity: thus far, most trials report relatively few signifi cant side effects. This
is likely due to the highly specifi c nature of oligo duplexing, and the fact that they are 'natural'
biomolecules. Some toxicity may, however, by triggered by non-specifi c binding to proteins, and
most antisense agents appear to promote pro-infl ammatory effects at high dosage levels.
The requirement for only low levels of the oligo to be present inside the cell, as target mRNA
is, itself, usually present only in nanomolar concentrations.
The ability to manufacture oligos of specifi ed nucleotide sequence is relatively straightforward
using automated synthesizers.
However, native antisense oligonucleotides also suffer from a number of disadvantages, which are ul-
timately responsible for numerous disappointing trial results, and the fact that, after almost two decades
of clinical investigation, only a single product has gained approval to date. Disadvantages include:
sensitivity to nucleases;
very low serum half lives;
poor rate of cellular uptake;
orally inactive.
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