Antisense Technology

What is Antisense Technology? The Science - How does Antisense Technology Work? Biotechnology and Antisense Technology Antisense Therapies in Development Bibliography Diseases are often connected to the insufficient or excess production of certain proteins. If the production of these proteins is disrupted, many diseases can be treated or cured. Antisense technology is a method that can disrupt protein production. It may be used to design new therapeutics for diseases in whose pathology the production of a specific protein plays a crucial role. What is Antisense Technology? In antisense technology, synthetically-produced complementary molecules seek out and bind to messenger RNA (mRNA), blocking the final step of protein production. mRNA is the nucleic acid molecule that carries genetic information from the DNA to the other cellular machinery involved in protein production. By binding to mRNA, the antisense drugs interrupt and inhibit the production of specific disease-related proteins. "Sense" refers to the original sequence of the DNA or RNA molecule. "Antisense" refers to the complementary sequence of the DNA or RNA molecule.

The Science - How does Antisense Technology Work? How are proteins made? Proteins are constantly being produced in the body. Protein production is triggered by various stimuli, such as hormones. It occurs in two steps: Step 1: Transcription During transcription, the genes (DNA) are copied into an intermediate molecule called messenger RNA (mRNA). Transcription occurs in the nucleus of the cell. The mRNA must be transported out of the nucleus into the cytoplasm of the cell where the second step, translation, occurs. Step 2: Translation This is the final step in protein synthesis, where mRNA acts as a blueprint to define the sequence of amino acids, which make up the final protein product.

How does Antisense Technology Work? The therapeutic objective of antisense technology is to block the production of diseasecausing proteins. This is achieved by creating a synthetic "antisense" or complementary nucleotide sequence of DNA or RNA that interacts with, and binds to the "sense" or original mRNA sequence. This "mRNA - antisense complex" can no longer be translated and the disease-causing protein cannot be produced. Biotechnology and Antisense Technology

The impact of biotechnology on antisense technology is expected to increase dramatically as the links between genetics, protein production and disease are better understood. Currently, antisense technology is used to design therapeutic compounds which target specific mRNA sequences to obstruct the production of certain disease-causing proteins. Traditional drug therapies focus on a drug's interaction with the disease-causing proteins. However, antisense drug therapies inhibit the production of the disease-causing proteins altogether. Antisense Therapies in Development Applications of antisense technology in therapeutics are expected to increase substantially as the link between diseases and genes are made. Antisense drug therapies are currently unavailable in Canada. However, there are numerous antisense therapies in development, some of which are in clinical trials, and one of which has been approved for use in the United States.

Antisense is an important technology for drug discovery and development. It is broadly used by the pharmaceutical industry as a tool for functional genomics and as highly specific drugs for a wide range of diseases. Cumulative clinical and preclinical data suggest that antisense technology has the potential to create a new sector of the pharmaceutical industry. Isis scientists have worked systematically and rigorously to address the questions associated with the development of this new drug discovery platform. Do antisense drugs interact with their RNA targets in a highly specific manner? Where do antisense drugs distribute in the body? Do they get into cells? What doses produce therapeutic effects? What are the potential toxicities, and how can they be minimized or avoided? How can antisense drugs be made more convenient for patients? What diseases can they treat? Based on extensive research conducted to answer these questions, Isis scientists know that antisense drugs possess the following characteristics:

Specificity:
The pharmaceutical industrys primary quest in drug discovery is drug specificity. The more precisely a drug interacts with its intended target, and not with unintended molecules, the more likely it is to produce a therapeutic effect without causing unwanted side effects. One of the most alluring attributes of antisense is its specificity. Antisense drugs interact with their intended target based on information in the genetic code. (Visit the basic science section of this site for a further discussion on how antisense drugs work.) In contrast, traditional drugs bind based on the shape of proteins and charge interactions, creating more opportunity for unwanted interactions, and, often undesirable side effects. Based on their specificity, antisense drugs have the potential to be safer than other types of drugs.

Broadly Applicable:
The nature of the antisense receptor, RNA, makes virtually any molecular target accessible to antisense drugs. There are many highly desirable molecular targets for drug discovery

that are considered undruggable by traditional small molecule technology. These targets are often members of families of closely related proteins that are too similar in structure for traditional drugs to distinguish amongst, the biological function of the protein is unknown, or it is difficult to develop an assay for drug screening. Antisense drugs discriminate between targets based on their genetic sequence, so the universe of potential targets is significantly greater. Isis scientists have performed hundreds of experiments to determine how and where antisense drugs distribute throughout the body. Research shows antisense drugs accumulate in specific organs and tissues, so Isis drug discovery research is focused on diseases that are associated with targets expressed in the liver, kidney, spleen, bone marrow and fat cells. Isis drug development programs are aimed at treating cardiovascular, metabolic and inflammatory diseases. Isis partners are focused in disease areas such as ocular, viral and neurodegenerative diseases, and cancer. The Companys researchers have also made significant progress in developing new formulations (aerosol, enema, intrathecal, intravenous, subcutaneous, intravitreal, oral and topical) of antisense drugs that expand the potential for antisense.

Rational Design:
Antisense drug discovery is more rational than any other type of drug discovery because: 1) The rules for creating these drugs are known, as they bind by hybridization to the target RNA. 2) The chemistry is constant, with only the order of the drugs nucleotides changing to make the drug target specific. 3) The distribution and metabolism of antisense drugs are very similar from drug to drug, resulting in a common and often times, predictable, safety profile across antisense drugs.

Efficiency:
The benefit of a more rational approach to drug discovery is efficiency. The efficiency of antisense results in shortened timelines to identify lead drug candidates in the discovery phase of development. The consistency of the behavior of antisense drugs allows Isis scientists to apply what they learn from the testing of one drug to future drugs, thus reducing the potential for failure in the early stages of development and creating significant competitive advantage for the platform. The efficiency of antisense technology is also realized in the area of manufacturing. Advances in process chemistry over the course of the Companys history have resulted in a dramatic reduction in the cost of Isis drugs. Isis built a state-of-the-art, commercial scale manufacturing facility, which was completed in February 2003. The facility is fully qualified and is capable of producing hundreds of kilograms per year of antisense drugs.