Fast-moving Antisense making new development links

By Tanya Hollis
Monday, 18 February, 2002

Newly listed drug discovery company Antisense Therapeutics has revealed it is tying up relationships with Australian and overseas institutes to develop its discovery pipeline.

Antisense, which has compounds in development for treatment of multiple sclerosis and psoriasis, is involved in developing synthetic genetic (antisense) molecules to block the production or over-expression of disease-causing proteins.

The new collaborations will build on Antisense's founding research partnerships with the Murdoch Children's Research Institute and Nasdaq-listed Isis Pharmaceuticals.

Research director Dr George Tachas said that while conventional drugs interfered at the protein level, antisense oligonucleotide drugs bound to messenger RNA inhibit synthesis of the proteins.

"If you think of it as being a war, traditional drugs are trying to shoot the planes out of the sky and we are knocking down the factories that make the planes," Dr Tachas explained.

To date, the pharmaceutical drugs on the market target a total of only about 500 different proteins. Although not all proteins will be suitable for therapeutic intervention,there is clearly enormous scope for drug discovery and new therapies with antisense technology, considering that the human genome contains codes for at least 30,000 different proteins.

But most global drug discovery efforts are often centered on trying to figure out how proteins fold in order to determine the chemical 'lock and key' system that leads to disease.

Dr Tachas said this costly process could take a year because of the number of possible variations each protein's 20 amino acids could adopt in the folding process.

He said that by taking a step back and focusing on the messenger RNA that is translated to proteins, drug design was much quicker because it involved only four nucleosides.

Dr Tachas said Antisense's partner Isis Pharmaceuticals could design antisense drugs within two hours, and identify optimised antisense compounds within a week ? results significantly faster than in conventional drug discovery.

But he said that use of the technology was not purely to reduce the time for drug discovery, and that antisense drugs were also expected to display a variety of medical advantages.

Dr Tachas said the antisense drugs could be delivered via a broad range of routes of administration, including aerosols and creams and delivery by devices such as stents. Oral administration is also being developed for humans.

He said they would also have benefits over antibody-based drugs that target the protein because they would not be rejected as foreign by the immune system or identified as foreign and neutralised.

"The pharmaceutical industry drives what is happening in drug research and they have traditionally always preferred to interfere at protein level," Dr Tachas said.

"What is happening now is there are too many opportunities at the genetic level to interfere at the protein level, so a variety of different technologies like antisense are now blossoming, to take advantage of the genetic revolution."

Antisense ? named for the fact that it binds to the sense information in the messenger RNA ? was conceived in the late 1970s and is now an advanced technology with stabilised nucleosides that are able to last longer in the body and have more predictable effects.

Dr Tachas said the company was on track to proceed into human trials of its antisense inhibitor to VLA-4 for the treatment of multiple sclerosis. Human studies with an antibody to VLA-4 demonstrated better efficacy than interferon ? the current standard in treating the degenerative disease.

He said Antisense was currently developing an antisense compound to the insulin growth factor 1 receptor as a potential psoriasis drug, to be tested by the Murdoch Children's Research Institute.

The combined value of multiple sclerosis and psoriasis drugs worldwide is more than $US5 billion.

Dr Tachas would not reveal details of the pending research partnerships, but said they would help push the company's project pipeline forwards in finding drugs for conditions ranging from infectious and metabolic illnesses through to cardiovascular disease and cancer.

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