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Ute Schepers – the therapeutic potential of small RNAs and molecular transporters

Small RNAs can specifically interfere with cellular mechanisms; or more precisely, with the cells’ protein biosynthesis machinery. Scientists have therefore decided to exploit this potential by using small RNAs against cancer cells or cells damaged in other ways. But the question arises as to how the small RNAs can reach the site where their role is to prevent the generation of dangerous proteins. Dr. Ute Schepers and her team from the Karlsruhe Institute of Technology (KIT) are focusing on the therapeutic potential of the small molecules and also on the use of molecular transporters that are able to transport their cargo solely to the predetermined target location, rather than anywhere else.

The method, which the researchers hope to be able to use in the future for the treatment of genetic diseases such as Huntington’s disease or cancer, is referred to as RNA interference (RNAi). RNAi is based on the ability of short RNA molecules (microRNA and small interfering RNA) to bind to complementary mRNA (messenger RNA) stretches and initiate the degradation of a particular mRNA. mRNAs are copies of protein-encoding genes or, more specifically, chemical “blueprints” for enzymes, structural and signalling molecules. Interfering RNAs are able to prevent the cellular production of specific proteins. And this is the effect the researchers hope to exploit in their quest to switch off the effect of defective, disease-related genes. “Only a small number of drugs are available for the treatment of rare diseases,” said Dr. Ute Schepers from the Institute of Toxicology and Genetics at the Karlsruhe Institute of Technology (KIT), going on to add “RNA interference is an excellent alternative to gene therapy as it enables us to specifically down-regulate overexpressed genes. However, RNA cannot just be injected into the blood circulation; it needs to be specifically transported to the damaged cells.”

Tempering the human immune system

Dr. Schepers is a chemist by training and has been investigating the potential of small RNAs for many years. In a recent project carried out with intensive care doctors, Schepers looked into how small RNAs can prevent organ failure in patients suffering from septic shock. Blood infections caused by multiresistant pathogens are rather frequent in intensive care wards; around 97 per cent of all sepsis patients suffer multiorgan failure and die. However, it is worth noting that these patients frequently die of heart failure as a consequence of their heart being attacked by the patient’s own immune system. “We investigated whether interfering RNAs can be used to down-regulate the CD14 receptor on the surface of cardiac cells,” said Schepers. “This receptor recognises bacterial cell wall components and alerts the immune system to the presence of intruders. This often triggers a harmful immune response.” Schepers and her team developed a small RNA that was able to prevent the production of the CD14 receptor in cardiac cells. However, before animal experiments could be intiated, Schepers and her team had to come up with a solution that enabled them to switch off the receptor in cardiac cells only.

Research group led by Dr. Ute Schepers (left) at KIT.
Research group led by Dr. Ute Schepers (left) at KIT. © Dr. Ute Schepers

Schepers and her team therefore searched for a way to transport RNA specifically into cardiac cells in order to prevent harmful immune reponses from occurring in other body tissues. These investigations also involved issues related to another of the team’s research projects, and the knowledge they have developed on molecular transporters based on peptoids or polyamines. Peptoids and polyamines are resistant to proteolysis, which makes them excellent cellular Trojan Horses. Like proteins and peptides, they are composed of amino acids. However, the chemical bonds between the individual amino acids differ slightly from the chemical bonds in proteins, which is why they cannot be recognised by the body’s degradation enzymes and be degraded. The surface of peptoids is equipped with special structures that only recognise complementary structures on the surface of target cells, which then engulf the peptoids. This enables a molecular transporter to migrate through the body unharmed and exert its action only in a specific cell. “We use special methods to attach small RNAs to such transport molecules, which then act as Trojan Horses and transport their cargo into the targeted cell type.”

The figure shows two complex chemical structures.<br />
Chemical structure of polyamines (left) and peptoids (right) used as molecular transporters. The red structure represents the cargo, for example a small interfering RNA molecule. © Dr. Ute Schepers

Right into the heart

“We succeeded in finding a transporter that is able to specifically transport the inhibiting RNA into the cardiac cells of mice, rather than into other cell types such as liver or spleen cells,” said Schepers. The researchers were able to prolong the lives of mice suffering from septic shock. However, in practice it is not particularly easy to develop a suitable molecular RNA transporter. The researchers need to use cell cultures to screen hundreds of potential molecules to find one that is able to specifically attach to and release its cargo into the cardiac cells. Once a suitable candidate is found, animal experiments are carried out to find out whether this particular molecule is actually able to find and enter the targeted organ.

In future, the researchers will need to test whether the method is also suitable for human application. Schepers and her team will continue working on their ongoing projects as well as focusing on elucidating how transporters and target cells are able to recognise each other. One issue they will focus on are cellular surface structures that are key in interacting with transporter molecules. However, the therapeutic application of small RNAs is still a long way off. Other researchers use RNAi technology in their search for methods to combat viral diseases such as hepatitis and HIV; some of these findings are already being tested in clinical trials. There is evidence that small RNAs are able to prevent the proliferation of viral proteins. “RNAi has become a powerful research tool that is used in thousands of laboratories around the world,” said Schepers. However, small RNAs will only be suitable for human application if intelligent transporter molecules that are able to find and enter damaged cells can be found.

Further information:
PD Dr. Ute Schepers
Institute of Toxicology and Genetics
KIT - Campus Nord
Hermann-von-Helmholz-Platz 1
76344 Eggenstein-Leopoldshafen
Tel.: +49 (0)721 /608 23444
E-mail: Ute.Schepers(at)kit.edu

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/ute-schepers-the-therapeutic-potential-of-small-rnas-and-molecular-transporters