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This is how oligonucleotides works

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We are at the beginning of a revolution that will change the way we develop pharmaceuticals. The first therapeutic oligonucleotides have been developed to treat unusual but serious genetic diseases, but we are now seeing a rapid development of the therapy for common diseases as well. Along with a number of partners, the University of Gothenburg contributes to this effort through the major initiative of the OligoNova Hub.

Therapeutic oligonucleotides are small molecules made up of the genome’s own building blocks, known as nucleotides. This new type of pharmaceutical targets the genes that need to be affected with great precision and without causing permanent changes in the genome.

The step between gene and protein

A gene in our genome almost always provides instructions for forming a certain protein in the cell. In a first step, the gene is translated into a messenger molecule, or mRNA, which is then transported to the site in the cell where proteins are produced. There mRNA acts as a template for what the protein is to look like. Altered genes result in incorrect protein templates, producing altered proteins that can cause many different diseases.

If researchers know exactly what genetic defects cause a disease, they often can create therapeutic oligonucleotides that can affect the translation from gene to protein. Therapeutic oligonucleotides can be tailored to shut down or alter the expression of genes. For example, they can be used to turn off the expression of a diseased gene, while leaving a healthy copy of the same gene unaffected.

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Many advantages

Most of the pharmaceuticals used today work by affecting proteins and their activity. This might involve stimulating receptors on the cell surface, for example. But in many cases, it can be very difficult to develop medications that can find a specific protein and affect how it works. This is an important problem in developing pharmaceuticals.

Therapeutic oligonucleotides provide another tool for researchers working in this area. The first steps in developing new medications can be done with the help of computers. Compared to traditional pharmaceuticals, it often takes much less time to develop new therapeutic oligonucleotides and it is easy to produce large amounts of these molecules. Researchers have also begun to understand how therapeutic oligonucleotides can be directed to specific cells in our body, although many challenges remain.

Temporary impact

Therapeutic oligonucleotides should not be confused with gene therapy, where the goal is to correct defects in the genome by introducing one or more new genes. When the therapeutic oligonucleotide is no longer administered, it disappears from the body and ceases to have an effect. No changes are made in the genome itself. Therapeutic oligonucleotides resemble ordinary medications in this respect. As a result, the regulatory framework that governs development of therapeutic oligonucleotides is more similar to that used in developing regular medications.

Explosive development

In recent years developments in this area have exploded. Twelve therapeutic oligonucleotides have been approved so far and more than 150 are in clinical development. To date, therapeutic oligonucleotides have been used primarily as a treatment for children with unusual genetic diseases. In a high-profile case involving an American girl with the deadly disease juvenile neuronal ceroid lipofuscinoses (Batten’s disease), treatment could begin with an effective therapeutic oligonucleotide developed in just one year.

The field of application of therapeutic oligonucleotides will also soon extend to common diseases, such as various forms of cancer, metabolic diseases and infections.