Moderna Therapeutics has published its first peer-reviewed study testing the safety of its messenger RNA (mRNA) molecules for therapeutic protein production in humans.
The small, Phase I trial, conducted in collaboration with AstraZeneca, showed that an experimental mRNA therapy called AZD8601 led to localized and temporary production of a therapeutic protein without severe side effects after it was injected into the skin of 33 men (Nat. Commun. 2019, DOI: 10.1038/s41467-019-08852-4). The trial is a stepping-stone to future studies in which mRNA will be injected directly into the hearts of people who have recently suffered a myocardial infarction.
Moderna is one of the most-watched biotech start-ups of the decade, raising more than $2.6 billion in private funds to create its mRNA platform and fill its pipeline with 21 experimental therapies. In December, the company raised more than $600 million in its initial public offering—the largest debut for a biotech company in Wall Street history—and today has a stock market value of close to $7 billion.
So far, investors have mostly relied on data from animal studies while placing their bets on Moderna. The company has already conducted early-stage clinical trials of experimental vaccines in which injections of mRNA encoding bits of proteins stimulate an immune response. The new publication with AstraZeneca, however, is the company’s first from a trial using mRNA to make fully-functional proteins that are therapies themselves.
The mRNA encodes a protein called vascular endothelial growth factor (VEGF) A, which stimulates new blood vessel growth. VEGF has been eyed as a potential regenerative medicine that could help cardiac tissue heal after a heart attack, but the idea hasn’t had much success yet. Injections of the protein alone don’t stick around long enough to have an effect. Some researchers have tried to permanently induce VEGF production in cells with DNA-based gene therapies, but this leads to too much VEGF and the formation of tumor-like structures.
For years, scientists have sought a way to tune VEGF levels to be not too high or too low. “mRNA is uniquely suited to do this,” says Tal Zaks, Moderna’s chief medical officer. Our bodies can use a single mRNA molecule to make many copies of VEGF proteins, but the VEGF won’t be made in perpetuity, as it is in gene therapies.
AstraZeneca and Moderna have already shown that VEGF mRNA has a restorative effect in the cardiac tissue of rats and pigs with heart attacks. “Injecting a new medicine into somebody’s heart is obviously something that you have to do very carefully,” Zaks explains, which is why for the Phase I safety study the companies injected the mRNA into the skin.
The men who got the highest dose had VEGF levels that were about 50% higher than normal within 6 hours of the injection. A day later, their VEGF levels near the injection site had returned to normal, indicating that the mRNA therapy was gone, but researchers measured heightened blood flow around the injection site that lasted for more than a week. That indicates the VEGF hung around long enough to kick-start a change in the local blood vessel physiology.
“This is a big step forward in the right direction for mRNA therapies,” says Lior Zangi, an assistant professor of cardiology at the Icahn School of Medicine at Mount Sinai. Zangi wasn’t involved in the new study, but he helped develop and test an experimental VEGF mRNA therapy in mice as a postdoctoral researcher at Harvard Medical School. That study helped lay the foundation for Moderna’s earliest programs.
The new study is proof that mRNA therapies can get into human cells and be translated into proteins, Zangi adds. “We assumed it would work but needed to prove it,” he says. “And there were no problems with safety,” which is what killed previous VEGF gene therapies.
Notably, the trial used naked mRNA without a special delivery vehicle. This may work well for localized injections of the molecule. For therapies that require injections into the bloodstream or need to distribute broadly through an organ, Moderna is packaging the mRNA into lipid nanoparticles, which shield the mRNA from the body and help sneak it into cells.
UPDATE: This story was updated on Feb. 20, 2019, to add comments from professor Lior Zangi.
The small study doesn’t prove that VEGF mRNA will help heal damaged cardiac tissue after a heart attack, and it doesn’t directly measure the formation of new blood vessels following VEGF injection. To get closer to answering those questions, AstraZeneca and Moderna are currently running a Phase IIa study testing their VEGF therapy in people undergoing open heart surgery for a coronary artery bypass.