New findings on mRNA therapeutics
Researchers at Charité – Universitätsmedizin Berlin and the BIH Center for Regenerative Therapies (BCRT) have gained new insights into immune responses to therapeutic mRNAs. Here, senior author and study lead Dr. Norman Drzeniek answers questions about the research findings.
What was the research question or scientific inquiry behind your study?
We know that mRNA-based therapeutics and mRNA vaccines can, under certain circumstances, stimulate inflammatory immune responses in the body’s own cells. To avoid an excessive inflammatory reaction, the mRNA can be modified chemically. Modified mRNA was also used in the mRNA vaccines against COVID-19. What has remained unclear so far is the extent to which the immune response to mRNA depends on the target tissue. In other words: does it make a difference whether the mRNA therapy is directed, for example, at the kidney or at phagocytic cells of the immune system?
How did you approach the topic?
We treated human cells from different tissues with mRNA and measured the inflammatory response of the various cell types. Since I also work with patients who suffer from severe autoimmune diseases, we were particularly interested in applying the mRNA to T cells. These are immune cells that are currently attracting a great deal of attention in rheumatology as part of so-called CAR T cell therapy, because they are considered a potential curative approach for autoimmune diseases. We are working on producing CAR T cells using mRNA, so their response to it is especially relevant to us.
What did you discover?
Cells of the innate immune system, so-called macrophages, reacted more sensitively to mRNA than cells from blood vessels, kidneys, and connective tissue. Even in macrophages, however, inflammation could be well controlled by modifying uridine, a component of the mRNA. This aligns well with our previous work, in which we investigated the importance of different uridine modifications in mRNA therapeutics.
Was there anything that surprised you?
The response of T cells to mRNA: we could not detect any! This truly came as a surprise to us, because until now it was thought that all cell types react to mRNA with inflammation and that such inflammatory responses must be prevented through complex mRNA modifications. The discovery of this principle was even awarded the Nobel Prize in Medicine in 2023. In T cells, however, such a reaction was absent or so minimal that it could not be detected.
What’s your takeaway?
The Nobel Prize-worthy principle of mRNA-triggered inflammation does not appear to apply to T cells. This is excellent news, because it means we do not have to worry too much about inflammatory side effects when using mRNA, for example to produce CAR T cells for our rheumatology patients. On the contrary: the CAR T cells were even more potent when generated using unmodified mRNA! This makes the production of this promising cell therapy significantly simpler and more cost-effective.
Contact
Dr. Norman Michael Drzeniek
BIH Center for Regenerative Therapies (BCRT) &
Department of Rheumatology and Clinical Immunology
Charité – Universitätsmedizin Berlin
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