In the midst of Berlin Science Week, biomedical and biotech experts will gather to discuss novel research results and new ways to translate science into clinical applications. Elsevier’s second Berlin Translational Dialogue will address the fascinating progress of RNA-based technologies and therapies with the aim of stimulating tangible developments that improve patients’ quality of life.
In this article, two of the guests speakers – Dr. Mariola Fotin-Mleczek, Chief Scientific Officer of CureVac, and Prof. Dr. Katalin Karikó, Vice President of BioNTech – discuss their companies’ general vision and projects that harness RNA for novel therapeutics.
Both scientists come with a proven track record in RNA research, having authored a multitude of peer-reviewed papers. At CureVac, Mariola Fotin-Mleczek is responsible for the development and practical testing of RNActive cancer vaccines and is named inventor of RNActive-related key patents. BioNTech’s Prof. Dr. Katalin Karikó has more than 30 years of experience working with RNA and is a distinguished inventor on multiple mRNA-related patents too. Prior to joining BioNTech, Prof. Kariko´ was a faculty member at the University of Pennsylvania, Medical School for over 25 years.
Why RNA for therapeutics?
Ribonucleic Acid (RNA) is believed to be the key molecule contributing to the origins of life on Earth. RNA appears in a variety of forms, has a complex metabolism and fulfills many distinct roles rather than merely serving as a messenger in the transfer of information from DNA to the protein. Intriguing discoveries in the last 10 years have brought numerous formerly unknown RNA species and functions to light, offering unprecedented insights into basic biology and opening new avenues for RNA-based therapies.
What inspired you to study RNA? What makes this molecule, in its very many forms and activities, so unique, so interesting?
Katalin Karikó: It was 1978 when, as a graduate student, I joined the RNA lab of Prof. Jenö Tomasz, who chemically synthesized cap analogs for Aaron Shatkin to identify the cap structure of the mRNA. As part of my thesis, I synthesized 2’-5’-linked oligoribonucleotides and tested their antiviral effects.
Later, between 1985 and 1988, while working at Temple University in Philadelphia, I participated in a clinical trial in which patients with AIDS, hematological diseases and chronic fatigue were treated with dsRNA. The molecular mechanism of interferon induction by dsRNA was not known, but the antiviral and antineoplastic effects of interferon were well documented.
In 1990, I submitted my first grant application in which I proposed to establish mRNA-based gene therapy. Ever since, the mRNA-based therapy is my primary interest.
Mariola Fotin-Mleczek: I “became infected” with the RNA vision by joining CureVac in 2006. My task at this time point was to demonstrate in the preclinic that mRNA therapy can help to fight cancer. I was extremely excited not only about the data we got in this area but about the very promising results coming from approaches in other fields. We realized very early that mRNA has the potential to be used very broadly und provide solutions for different diseases.
How important are innovative technologies in RNA biology?
Mariola Fotin-Mleczek: RNA technology is a very innovative one. The innovation is required to transform mRNA into potent drugs. We have to understand RNA biology, its chances and limitations, to be able to learn from nature and to improve the molecule to make it strong for the use in human.
How do you use RNA-technologies to improve people’s health?
Katalin Karikó: We use mRNA-based vaccination to treat cancer and to prevent and treat infectious diseases. We will use mRNA encoding therapeutic proteins to treat acute and chronic diseases.
What is special about RNA technologies, and what advantages does it offer in the cure or prevention of diseases?
Katalin Karikó: RNA can be generated in a large amount very quickly, which is a great advantage for global vaccination against emerging infectious diseases. Local single injection of the mRNA can ensure local secretion of the encoded therapeutic protein for long duration.
Mariola Fotin-Mleczek: The huge potential of RNA technology is connected to the flexibility we have by creating new medicines on this base. When we are designing mRNA molecules on our laptops we can decide about the fate of encoded protein, about its cellular localization in the body, about its half-life, about the interaction with other proteins, even intracellular ones. We can easily combine different mRNAs to potentiate effects we want to achieve. In the field of prophylactic vaccines we can address virus diversity, rapidly adapt the sequence according to circulating virus strains or even design vaccine cocktail directed against multiple pathogens. But independent how our final sequence will look like, the production process is always the same and this platform character of mRNA manufacturing makes this technology even more attractive.
What do you see as some of the risks or major hurdles in applying RNA-based therapies?
Katalin Karikó: The most important is to proceed with great care and make no harm when RNA is used for therapy. We can generate RNA that doesn’t activate the immune sensors when it enters into the cell. However, RNA is not an inert molecule. RNA that is not taken up by cells remains extracellular and can promote blood coagulation and vessel permeability. In addition, unnatural modified nucleosides present in selected RNA with therapeutic intent can also be potentially toxic for mitochondria.
What is needed to globally boost RNA research and translation?
Katalin Karikó: RNA has been tested in clinical trials for 40 years and no RNA therapeutics are in clinical practice today. Providing more financial support for academic researchers as they are more likely to investigate the effect of RNA in its complexity.
From your perspective, which role does Germany play in the global RNA research landscape?
Katalin Karikó: Germany has a very strong position both in RNA research as well as the therapeutic development fields.
Mariola Fotin-Mleczek: My personal hope and belief is that Germany will play an important role in the RNA landscape. The idea to use mRNA as a therapy was born in Germany and we should bring the first mRNA medicine to the market. To have strong smart mRNA products innovation is still required and we have talented and dedicated people here, there is no need to let the others make the final step. I hope we will have enough power and get the financing to set the label “made in Germany” on it.
CureVac stands for diverse therapeutic possibilities (cure) based on revolutionary vaccination (vac). The biopharmaceutical company explores and develops versatile RNA technologies focused on cancer treatments and protection against infectious diseases. CureVac was founded in 2000 and is based in Tübingen and Frankfurt a.M., Germany, with 2015 opened operations in Cambridge, Massachusetts, USA.
Founded in 2008 and based in Mainz, Germany, BioNTech is pioneering innovative technologies in the field of mRNA based medicines. As a fully integrated biotech company, BioNTech combines all aspects of immunotherapies in one place. BioNTech currently boasts approximately 450 employees and is a privately held company.
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