The replacement of uridine by 1-methylpseudouridine helped mRNA vaccines against COVID-19 to achieve significantly improved pharmacological properties. However, the limited shelf life and laborious formulation in liposomes complicate the production and presumably on the efficiency of mRNA vaccines. It can be expected that further modifications will allow considerable optimizations. The focus of this project is the advancement and use of chemical modification of nucleotide positions of the mRNA (based on click chemistry) as well as the generation of polycistronic mRNAs in order to be able to vaccinate against co-existing virus variants with the aid of a single vaccine.

Hepatitis B is a very common chronic viral disease that is difficult to cure. The established therapy is based on the use of nucleoside analogous that can control virus replication but are not curative. Interferon alpha may cure hepatitis B, but is accompanied by high side effects as it is applied systemically. The aim of this sub-project is to package interferon-encoding mRNAs into nanoparticles and deliver them directly to HBV-infected livers.

WP9 is dedicated to cardiovascular diseases, in this case in the context of skeletal muscle disease. Specific guide RNAs for CRISPR/Cas-based gene therapy of DMD will be developed and formulated into nanoparticles. Initially, the therapy will be studied experimentally in organoid models before final validation in large animal models. Since the dystrophin gene responsible for DMD is located on the X chromosome, WP9 also aims to activate the intact dystrophin allele on the second (inactive) X chromosome by manipulating epigenetic factors.

WP8 addresses two significant and often fatal cardiovascular diseases: Carotid artery stenoses and aneurysms of the abdominal aorta. In both cases, changes in vascular structure are causative for the disease. Preliminary work on WP8 already showed that a small non-coding RNA, the microRNA miR-126-5p, in the cell nucleus can assume an unusual function as an RNA aptamer that has a protective effect on endothelial cells. Here, the binding of the microRNA to the protein Mex3A is crucial. The aim of this WP is to develop aptamers that preferentially bind to Mex3A and, based on this, to develop drug-eluting stents that release the aptamer as a protective agent.