RNA-based Therapeutics

RNA molecules play a critical role in a wide range of biological processes, including the initiation and progression of diseases. As a result, RNA-based therapeutics have emerged as promising candidates for treating various diseases. These therapies harness the power of RNA to modulate gene expression or influence epigenetic, posttranscriptional, and translational pathways.

Two primary approaches are utilized in RNA-based therapeutics: gain-of-function and loss-of-function strategies. Gain-of-function approaches focus on increasing the expression of a target gene, while loss-of-function approaches aim to inhibit or silence specific target molecules.

For the modulation of targeted gene expression, various strategies are available nowadays including viral and non-viral approaches. Recombinant viral systems including lentiviruses or adeno-associated viruses (AAV) are commonly used for gene delivery both in vivo and in vitro. These viral systems allow for the overexpression or silencing of target gene sequences when combined with oligonucleotides.

Oligonucleotides such as modified mRNAs (modRNAs), RNA inhibitors (siRNAs, GapmeRs, locked nucleic acids) or RNA mimics can also be utilized in a non-viral therapeutic approach. These synthesized molecules can be given through various routes of administration. Several groups are optimizing organ-specific RNA delivery approaches.

The development of novel RNA-based therapeutic strategies targeting disease is a multistep process combining various screening and validation approaches in vitro/ex vivo, in vivo and in human patient material. In our laboratory, we have identified several promising therapeutic strategies for the treatment of cardiovascular diseases. These strategies are currently undergoing further preclinical development or have already been licensed to biopharmaceutical companies. A recent success is the acquisition of our RNA-based spin-off company Cardior Pharmaceuticals GmbH by Novo Nordisk (2024).

Key References:

Viereck, J., Bührke, A., Foinquinos, A., Chatterjee, S., Kleeberger, JA., Xiao, K., Janssen-Peters, H., Batkai, S., Ramanujam, D., Kraft, T., Cebotari, S., Gueler, F., Beyer, AM., Schmitz, J., Bräsen, JH., Schmitto, JD., Gyöngyösi, M., Löser, A., Hirt, MN., Eschenhagen, T., Engelhardt, S., Bär, C., Thum, T. (2020) Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy. European Heart Journal. 41(36):3462-3474. https://doi.org/10.1093/eurheartj/ehaa519

Lu, D., Thum, T. (2019) RNA-based diagnostic and therapeutic strategies for cardiovascular disease. Nature Reviews Cardiology. 16(11):661-674. https://doi.org/10.1038/s41569-019-0218-x

Foinquinos, A., Batkai, S., Genschel, C., Viereck, J., Rump, S., Gyöngyösi, M., Traxler, D., Riesenhuber, M., Spannbauer, A., Lukovic, D., Weber, N., Zlabinger, K., Hašimbegović, E., Winkler, J., Fiedler, J., Dangwal, S., Fischer, M., de la Roche, J., Wojciechowski, D., Kraft, T., Garamvölgyi, R., Neitzel, S., Chatterjee, S., Yin, X., Bär, C., Mayr, M., Xiao, K., Thum, T. (2020) Preclinical development of a miR-132 inhibitor for heart failure treatment. Nature Communication, 11(1):633. https://doi.org/10.1038/s41467-020-14349-2

Abbas, N., Haas, JA., Xiao, K., Fuchs, M., Just, A., Pich, A., Perbellini, F., Werlein, C., Ius, F., Ruhparwar, A., Fiedler, J., Weber, N., Thum, T. (2024) Inhibition of miR-21: cardioprotective effects in human failing myocardium ex vivo. European Heart Journal. 45(22):2016-2018. https://doi.org/10.1093/eurheartj/ehae102

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