When Ingmar Hoerr suggested to his colleague Michael Kormann, a professor at the University of Tübingen, that they should organize a workshop to bring together researchers working on messenger RNA (mRNA) therapeutics, he expected it to be a rather intimate event with about 30 attendees. So it was a pleasant surprise when the first International mRNA Health Conference, which was held last week at the University of Tübingen in Germany, attracted more than 120 participants.
“A lot of pharma guys were there as well, from Pfizer, Sanofi and Takeda,” says Hoerr who was one of speakers at the event and is the CEO and co-founder of CureVac, a biopharmaceutical company that is developing mRNA vaccines. “It was quite interesting to see that there is an awareness in pharma about this new technology.”
During the 1990s, Hoerr and colleagues discovered that when you placed RNA into the skin, the skin cells began to express the encoded proteins. “That was really unexpected because everyone thought that RNA was unstable,” says Hoerr. “Everyone was hesitant to work with RNA at the time.” Instead, most researchers were focused on developing gene therapy using DNA molecules, which eventually ran into significant roadblocks and never lived up to its potential.
But Hoerr’s group found that RNA was actually quite stable when not in the presence of RNases that quickly degrade the RNA molecules. The molecule is so stable, in fact, that it can be kept at room temperature for at least two years without experiencing significant degradation. Seeing potential in mRNA therapeutics, Hoerr and colleagues founded CureVac to reinvent a safer gene therapy with RNA molecules.
Since then, the researchers at CureVac have been advancing their mRNA technology. So far, they have two clinical trials in progress: one for prostate cancer, another for non-small cell lung cancer. In addition, they are already collaborating with pharmaceutical company Sanofi Pasteur, In-Cell-Art and the Defense Advanced Research Projects Agency (DARPA) on a $33.1 million project to develop vaccines for infectious disease. And just this past month, the company entered into a collaboration with Janssen Pharmaceuticals to develop an mRNA-based influenza vaccine.
At the conference, a clear division in the application of this technology was evident. Some, such as Hoerr and his colleagues, are using the technology to illicit an immune response. In this strategy, antigen-encoding mRNA are injected into the patient’s body, and then the patient’s cells take up the mRNA, express it and produce an immune response against the disease. In CureVac’s early cancer trials, over 80 percent of patients treated with their mRNA vaccines have had a specific immune response against their tumors, increasing the median survival rate from 15 to 30 months, according to Hoerr. “Of course, these studies are much too small, and not controlled, to be a proof-of-concept, but it’s an indication that something right is happening in the patients,” says Hoerr.
Meanwhile, others such as Kormann are developing mRNA therapeutics from an enzyme replacement approach. The idea here is to deliver the mRNA to a specific tissue that will then express the protein of interest. For example, in a paper published earlier this year in the Journal of Clinical Investigations, Kormann and colleagues demonstrated that they could help protect allergen-induced asthma episodes in mice lungs through a novel mRNA therapeutic that helped to balance helper T-cells responses.
Of course, big pharma has invested in RNA before, specifically in RNA-interference (RNAi) therapeutics, which did not pan out overall for a number of reasons. For one thing, silencing protein production through RNAi requires a significant number of short interfering RNA (siRNA) in the cell. But to express proteins, only a small number of mRNA copies are required for the therapy to be effective.
One of the biggest issues with RNAi is the delivery of the molecules into cells, but mRNA is taken up into cells through an active mechanism, so delivery becomes less of a challenge. With the immune response, any cells in the body can produce an immune response, so targeting a specific tissue is a not an issue. And with the enzyme replacement, you just need to ensure that the target tissue takes up the mRNA template.
In addition, each protein can be encoded by an mRNA, which can be combined, so the platform allows for treatments that hit multiple targets, which could produce more effective treatments than drugs designed to hit a single target. “It doesn’t matter what you encode in RNA, meanwhile we gained the experience to encode more than 1000 different proteins on RNA, each of them was translated properly in vitro or in vivo,” says Hoerr.
As for the conference, the organizers are already planning a bigger and better conference for next year to capitalize on the momentum of the first one. “There were a lot of good discussions at the conference. It’s interesting to see something moving here,” says Hoerr.
Filed Under: Drug Discovery