Technology Overview
After 20 years of technology refinement, antisense is a mature drug discovery and therapeutic platform.
Introduction
Several antisense drugs are now in late stage clinical development with one antisense drug developed by Isis, Vitravene®, marketed in the US and Europe.
With access to Isis Pharmaceuticals’ proprietary drug discovery process as illustrated in the diagram, Antisense Therapeutics Limited can move quickly from drug discovery into developing therapies. Once we have identified a therapeutic application and corresponding gene target, an antisense lead inhibitor compound can be rationally designed within hours suitable for use in research and clinical trials. This compares with traditional drug discovery approaches which can take years to produce such a lead compound. Antisense drug development also benefits from uniform methods of manufacture, formulation and delivery of antisense compounds.
At the same time, the explosion of genetic information provided by the completion of the Human Genome Project (HGP) provides a rich resource of information on target genes for the design of antisense drugs.
Vitravene is a registered trademark of Novartis AG.
Genes, proteins and the drug discovery process
Cells are small membrane-enclosed compartments containing a host of structures and biochemicals made of proteins or by the action of proteins. The genetic blueprint for the production and control of these structures and biochemicals is found in the nucleus of the cell, where the chromosomes contain about 30,000 genes, collectively called the human genome.
Each of our genes is a set of instructions for, and control of the manufacture inside the cell of a unique protein. Some proteins form the cell structure, while others are enzymes that carry out the functions of the cell or hormones interacting with the external environment of the cell.
Most pharmaceutical drugs available today interact with one or more proteins. They act to enhance or inhibit the action of a protein or mimic its role thereby bringing about the specified therapeutic effect.
To date the pharmaceutical drugs on the market target a total of only about 500 different proteins. Although not all proteins will be suitable targets for therapeutic intervention, there is clearly enormous scope for drug discovery and new therapies in this post genomic era, considering that the human genome codes for at least 30,000 different proteins.
As technologies progress in the medical sciences, newer, more specific and rapid means of drug discovery are emerging – antisense is one of these emerging technologies.
How antisense compares with conventional drugs
The approximately 30,000 genes in our human genome can be transcribed into about 85,000 different mRNA, each used in the cell as a template to synthesise a different protein. Conventional pharmaceutical drugs (small chemicals), peptides, or proteins (for example, hormones), and antibodies (which are very large proteins) typically bind to the target protein directly to treat a disease.
Antisense drugs are designed to bind to the mRNA of a target protein, inhibiting the protein production process. The completion of the sequencing and initial analysis of the human genome through the HGP provides a resource for the design of antisense drugs without requiring the complex and time consuming analysis of the structure of the target protein which is required for conventional (small molecule) drugs.
How antisense works
The antisense concept was first conceived in 1978 and has been through various technical refinements. Antisense compounds are designed to have the right nucleotide sequence to bind specifically to and interfere with its associated mRNA, the instructions for the production of a particular protein. To create antisense drugs, special chemically stabilized nucleotides are synthetically linked together in short chains of about 12-30 nucleotides (called oligonucleotides). Each antisense drug is designed with the right complementary genetic code to bind to a specific sequence of nucleotides in its mRNA target to form a short area of double strands.
This double stranded region can inhibit the production of protein by a number of mechanisms. They include stopping the ribosome from reading the message, or by leading to the destruction of the mRNA by an enzyme already in the cells called RNase H. Rnase H present both inside and outside of the nucleus, destroys any such double-stranded nucleotides.
Conclusion
The rapid development of antisense technology offers almost unlimited scope for the development of new and highly specific therapeutics. Antisense Therapeutics therefore is well positioned to play a significant role in the progression of antisense technology for drug development in human diseases.
