Ionis has led the pharmaceutical industry in the development of a new drug class called antisense oligonucleotides. These drugs exert their effect by targeting RNA (“RNA Therapeutics”) resulting in the silencing of disease causing genes (‘gene silencing’). They decrease protein production by the target gene, and thus silence its effects, rather than repairing a faulty gene or targeting the protein. Ionis Pharmaceuticals is the only company to have RNA Therapeutics-based drugs approved for treating patients. Furthermore, Ionis currently has a wide variety of antisense oligonucleotide drugs at various stages of pre-clinical and clinical development.
These drugs aim to treat a diverse spectrum of different diseases, including conditions for which there are no traditional drugs available. Antisense oligonucleotide drugs that are currently being developed by Ionis include drugs to treat heart disease, metabolic diseases, cancer, inflammatory diseases and severe and rare diseases.
Proteins are the basic building blocks of life. All the cells in our bodies are constructed out of a variety of different proteins, each of which is specialized for a particular function. The muscles, bones, skin, hair and internal organs are made of proteins, as are the enzymes, hormones and antibodies that are necessary for healthy body function.
All proteins are produced in cells by a process called gene expression, in which the information present in the genetic code is used to build proteins. In order to understand this process, it may be helpful to consider the stages necessary to build a house. The DNA molecules which make up the genes in the nucleus of each cell in the body are like the architect’s blueprints. Other molecules that are also present in all cells act like the various bricklayers, electricians and plumbers who need to read and follow the blueprints and communicate effectively together to ensure that the house is built in accordance with the blueprints. These molecules which effectively follow the instructions in the DNA are called messenger RNA (mRNA) and transfer RNA (tRNA). DNA and RNA are made of nucleotides and proteins are made of amino acids.
The first step in protein production is called transcription. In this process the information contained in the DNA is conveyed out of the nucleus by an mRNA molecule containing protein building information in the language of genetic code. The next steps involve complex interactions between mRNA and tRNA whereby the genetic code language is translated into the language of amino acids, which are the building blocks of proteins.
Protein production may go wrong in a variety of ways and cause a variety of diseases. Some diseases are caused when the regulatory mechanisms that control protein production go wrong and there is uncontrolled overproduction of a normal protein. Other diseases are caused by faulty genes. Just as a mistake in the architect’s blueprints may cause a dangerous error in the construction of a house, a gene alteration (mutation) can cause cells to produce an abnormal, disease-causing protein.
For the last 100 years, medical researchers and the pharmaceutical industry have focused on the discovery and development of drugs that bind to faulty and disease causing proteins in order to modify their effects. Antisense technology represents a major paradigm shift in drug development, towards a focus on silencing the genes for disease-causing proteins.
Antisense oligonucleotide drugs are DNA- or RNA- like molecules consisting of a short string of nucleotides (the building blocks of DNA and RNA). For each target disease, Ionis scientists have engineered an antisense oligonucleotide drug that is exactly complementary to the part of the mRNA molecule that contains the genetic information for building the protein that causes that disease. So the drug binds tightly only to the specific mRNA molecules targeted and prevents the next stage in protein building, where the genetic information is translated into the amino acid sequence of the disease-causing protein. Once the drug has bound to the mRNA, protein production may be prevented by different mechanisms, most frequently by destruction of the mRNA by an enzyme in the cell (called RNaseH). Thus the antisense drug can effectively prevent or dramatically decrease production of the disease-causing protein.