ANTI SENSE DRUGS
Antisense drugs are drugs that seek to block DNA
transcription or RNA translation in order to moderate many disease processes.
Antisense drugs consist of nucleotides linked together in short DNA or RNA
sequences known as oligonucleotides.
Oligonucleotides are designed knowing the target DNA/RNA to
bind to specific DNA or RNA sequences or regions (eg, messenger RNA) to block
transcription or translation of that targeted protein. An oligonucleotide that
binds complementary (“sense”) mRNA sequences and blocks translation is referred
to as antisense.
To further stabilize the drug, many chemical modifications
have been made to the oligonucleotide structure. The most common modification
used involves substitution of a nonbridging oxygen in the phosphate backbone
with sulfur, resulting in a phosphorothioate-derived antisense oligonucleotide.
Some of these drugs have been designed to target viral disease and cancer cells
in the body.
Antisense drug
discovery and research & development.
For this approach to be useful, the etiology and genetics of
the disease must be known. For example, in the case of viral infection, known
sequences belonging to vital genes can be targeted and inhibited by antisense
drugs. Many antisense sequences are usually tested to find the best candidate,
since intra- and intermolecular interactions can affect oligonucleotide
activity and delivery. Though oligonucleotides are relatively well internalized
compared to rDNA molecules, cellular uptake is often low enough to require
delivery systems, such as liposomes. Antisense and gene therapy approaches have
also been combined using viral vectors to deliver an antisense sequence. In
this case, the transgene is transcribed into an mRNA molecule that is antisense
and therefore binds to the target mRNA. The resulting RNA:RNA interaction is
high affinity and results in inhibition of translation of that mRNA molecule.
History of antisense
drugs
In the early 1970s, Paul Zamecnik (pronounced ZAM-es-nick)
was studying a cancer-causing chicken virus that transmits its genetic
information via RNA, a chemical cousin of DNA. Zamecnik and his colleagues at
Massachusetts General Hospital found that, as the virus replicated, its RNA
looped around on itself. They speculated that if they could block this step,
they could stop the bug in its tracks. So they constructed a short piece of DNA
designed to stick to the virus’s single strand of RNA and thereby gum up its
works. The RNA encoded the virus’s proteins; functionally, it made sense, so
the researchers called it the “sense” strand. The DNA molecule (called an
oligo-nucleotide) was its chemical opposite-the “antisense.” Zamecnik mixed the
designer DNA snippet with infected chicken cells, and voil-no cancer. He and
colleague Mary L. Stephenson suggested that antisense molecules could be used
to treat all sorts of infections-as well as cancer-by preventing RNA from being
translated into the proteins the invaders need to live.
When the work
appeared in the January 1978 Proceedings of the National Academy of Sciences,
no one believed the experiment had worked. “It had been…a dogma that
oligonucleotides didn’t get into cells,” Zamecnik says. The work languished in
obscurity until the mid-1980s, when technological advances made the experiments
easier to repeat. As biochemists began to see anti-sense as a magic bullet,
companies sprang up to capitalize on the “new” technology. It wasn’t smooth
sailing-difficulties with stability and specificity to targeted RNAs hindered
its adoption. But now the technique seems ready to pay off.
On 24 August 1998, the US Food and Drug Administration (FDA)
approved the world’s first antisense drug, fomivirsen, developed by Isis
Pharmaceuticals Inc. , a small
biotechnology company based in Calsbad, California. The FDA approved the drug
for the treatment of CMV retinitis, a viral infection that causes blindness in
AIDS patients. Following Isis’ success, there is now increasing interest in
antisense technology. Isis is currently conducting ongoing clinical trials of
other antisense drugs for the treatment of common medical conditions, including
rheumatoid arthritis, cancers and Crohn’s disease, a serious intestinal
illness.
More than 20 other antisense drugs, most targeting cancer
and viral infections, are in clinical trials. And Zamecnik (the founder of
Isis), now nearly 90 years old, is still researching antisense treatments for
drug-resistant forms of tuberculosis and malaria.
