ANTI SENSE DRUGS

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.