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Technology overview


Antisense technology represents an important breakthrough in the way we treat disease. The explosion in genomic information led to the discovery of many new disease-causing proteins and created new opportunities accessible only to antisense technology.

With access to Ionis Pharmaceuticals’ proprietary drug discovery process as illustrated in the diagram, the Company 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..

Antisense is an innovative platform for drug discovery. Platform technologies combine all the elements necessary to rapidly and efficiently create a stream of new products..

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.

Antisense drugs are rapidly and effectively absorbed in the blood, antisense drugs bind loosely to proteins. This binding facilitates their distribution to tissues and prevents immediate loss in urine. In tissues, the drugs are cut by endonucleases, the drugs may be further degraded by exonucleases. The partial drug molecules do not bind to proteins and are therefore cleared in the urine.

Like all drugs, antisense drugs can have side effects. The side effects are generally predictable, occur at high doses and are well understood. More than 6,000 humans have been safely treated in trials conducted by Isis and its partners.


The rapid development of antisense technology offers almost unlimited scope for the development of new and highly specific therapeutics. Percheron Therapeutics therefore is well positioned to play a significant role in the progression of antisense technology for drug development in human diseases.