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Nachrichten, Termine, Experten
Nachrichten, Termine, Experten
At the RNApp graduate school, young researchers are working to make RNA-based drugs safer and more effective.
Ribonucleic acid (RNA) is an important component of our cells. As messenger RNA (mRNA), it is the blueprint for translating genetic information into proteins. This process can also be used medically to produce specific proteins. One well-known application is mRNA vaccines against coronaviruses. There is also so-called non-coding RNA (ncRNA), which does not contain protein blueprints but instead takes over control mechanisms in the cells, thus offering innovative starting points for new treatment methods. However, a particular challenge for all RNA-based therapies lies in the substance itself: RNA is unstable and breaks down quickly in the body. The RNApp research training group is looking for solutions to this problem. In twelve doctoral projects, young scientists from the fields of medicine, natural sciences, pharmacy and engineering are working on various issues related to the production, packaging and dosage form of RNA in individual sub-projects.
The aim of the joint project is to transfer the results from basic research into clinical practice and to make RNA-based drugs more effective, stable, safe and easier to use in the future. Professor Thomas Thum, Director of the Institute for Molecular and Translational Therapy Strategies at Hanover Medical School (MHH), is coordinating the project as a whole. Two subprojects are based at MHH, one of which is concerned with transporting an RNA active agent against fibrosis formation in the heart to the precise target site and releasing it there. The second subproject aims to use mRNA to elucidate the molecular mechanism by which the enzyme telomerase protects heart muscle cells from damage. The project is being supported by the state of Lower Saxony and the Volkswagen Foundation with 3.2 million euros. Of this, the MHH will receive around 800,000 euros.
Decades of experience in RNA research
Professor Thum has decades of experience in RNA research and has published many scientific papers on the use of coding and non-coding RNA for medical applications. According to the current list of ‘Highly Cited Researchers’ compiled by Clarivate Analytics, he is one of the world's most frequently cited scientists and is listed in the ‘Cross Fields’ category, in which researchers have an influence on science beyond their own field of work. In addition, a clinical study is currently testing an RNA-based agent developed by him that can not only stop heart failure but even reverse it. One hallmark of heart failure is the stiffening of the heart muscle due to the deposition of connective tissue cells, a condition known as fibrosis.
Novel transporter delivers RNA directly to its destination
This is the starting point for the subproject in which biomedical scientist Franziska Herbig is working under the leadership of Dr. Franziska Kenneweg. ‘We want to use a completely new nanoparticle system to transport the therapeutic RNA directly to the target tissue and only release it there,’ emphasises the doctoral student. Unlike RNA vaccines, for example, the 25-year-old scientist does not use lipid nanoparticles as packaging. Instead, she uses nanoparticles with a magnetic, iron-containing core, known as superparamagnetic iron oxide nanoparticles (SPIONs) in technical jargon. ‘As an active agent, we use an ncRNA that silences a specific target RNA in the heart and thus suppresses fibrosis,’ she explains.
Heat controls release
The ncRNA is coupled to the SPION transport vehicle via a heat-sensitive connector and guided to the target location using a magnetic field. Once enough active ingredient has accumulated in the heart muscle, the iron-containing particle core is heated electromagnetically and the heat-sensitive connector releases the ncRNA. ‘The ncRNA is inactive as long as it is bound to the SPION transporter and only becomes active after it has been released,’ says the doctoral student. “We use a special imaging technique, similar to an MRI, to monitor the concentration of the active substance in the heart and the controlled release of the ncRNA.” The method is universal and can also be used with other RNA active substances and in other organs.
Protecting the power plants of heart cells
The second subproject also focuses on the heart. Here, biologist Peter Spenger is investigating how the enzyme telomerase protects the mitochondria in the heart muscle cells. This work is based on the research results of Professor Dr Christian Bär, who is also supervising this sub-project. Telomerase actually protects the ends of the chromosomes on which our genes are located from damage and shortening during cell division. This way, the cell retains its ability to divide and does not age. Under certain stress conditions, however, the enzyme can perform another function. ‘Telomerase occurs in connection with the mitochondria, which act as small power plants in the heart muscle cells to provide the energy for the pumping function,’ explains the doctoral student. The interaction between enzyme and mitochondria occurs via a telomerase component called TERT. This protects the cell power plants from damage caused by aggressive oxygen compounds.
Making the mechanism visible under the microscope
‘We want to clarify how and under what conditions TERT is channelled into the mitochondria,’ explains the 27-year-old junior scientist. To do this, he wants to produce mRNA with the TERT blueprint and package it in lipid nanoparticles. These will then be introduced into heart muscle cells generated from stem cells and examined using super-resolution microscopy. For this part of the work, the doctoral student will then move to the highly specialised research group ‘Structure and Dynamics of Mitochondria’ at the Department of Neurology at the University Medical Centre Göttingen.
Research in a network
In addition to MHH, Leibniz University Hannover, Technische Universität Braunschweig, the University Medical Center Göttingen and the Fraunhofer Institute for Surface Engineering and Thin Films are also involved in the RNApp research training group. In terms of content, RNApp is divided into three research areas: the development of RNA lipid nanoparticles (RNA-LNP), the drying and packaging of RNA and the integration of RNA in implants. Each of these clusters consists of several individual projects with specific focuses. A total of five sub-projects are based at MHH, which is also responsible for coordinating the graduate school.
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For further information please contact Professor Dr Dr Thomas Thum, thum.thomas@mh-hannover.de.
Researching for better RNA drugs: Doctoral student Franziska Herbig and doctoral student Peter Speng ...
Copyright: Karin Kaiser/MHH
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Researching for better RNA drugs: Doctoral student Franziska Herbig and doctoral student Peter Speng ...
Copyright: Karin Kaiser/MHH
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