As the first vaccines for Covid-19 rolled out at the end of 2020, messenger RNA catapulted into public awareness. Now, a few years later, interest in mRNA has exploded. Clinical trials are underway for dozens of mRNA vaccines, including ones for flu and herpes. And scientists are hoping to use mRNA to treat disease, not just prevent it. One of the biggest targets is cancer.
But a major obstacle is how to deliver the molecule to the place in the body that needs to be treated. Fatty bubbles called lipid nanoparticles can carry RNA into cells, and they can ferry it to a wide range of tissues but not to anywhere specific. That’s a problem for cancer, says Jacob Becraft, cofounder and CEO of Boston-based Strand Therapeutics, because many cancer treatments “can be incredibly toxic in off-target tissues.” But his company may have found a solution.
Strand has figured out how to “program” mRNA much like computer code, allowing it to perform certain functions—such as turning on only in specific cell types, at specific times, and in specific amounts. Today, the biotech company announced that the US Food and Drug Administration has greenlit a clinical trial testing the approach in cancer patients with solid tumors. Strand plans to begin enrolling patients this spring. It will be the first time a programmable mRNA therapy will be tested in people.
Naturally found in every human cell, mRNA carries the genetic blueprints for making the proteins our bodies need to function. The synthetic versions used in Pfizer and Moderna’s Covid vaccines provide instructions to make a lookalike coronavirus spike protein. Immune cells in the arm muscle recognize the spike protein as foreign and sound the alarm. The immune system mounts a response and generates protective antibodies against it. That way, when the body encounters the spike protein on the actual Covid virus, it’s primed and ready to fight it.
Using mRNA to treat cancer works in much the same way. Tumor cells notoriously evade the immune system, going undetected. But synthetic mRNA can direct cancerous cells to make certain proteins that alert the immune system to the tumor’s presence.
Strand’s therapy uses mRNA to make an inflammatory protein called interleukin-12, or IL-12, that causes immune cells to spring into action and unleash a cascade of events that kill cancer cells when and where they detect the protein. “What our mRNA does is go into the tumor, and then it causes that protein to be secreted by the tumor,” Becraft says. “The tumor essentially becomes a factory.”
Researchers have long eyed IL-12 as a potential cancer therapy. But in the 1990s, early trials of IL-12 were halted when patients experienced toxic side effects. In those studies, the protein was delivered directly into the bloodstream, which activated a severe inflammatory response throughout the body. Several companies have tried to make safer versions of IL-12, but interest from Big Pharma seems to be waning. Last year, Bristol Myers Squibb dropped its effort, with AstraZeneca and partner Moderna following suit.
To keep IL-12 inside tumors, scientists at Strand designed a set of instructions called a genetic circuit that tells the mRNA to make the inflammatory protein only when it detects the tumor microenvironment. The circuit is designed to sense levels of microRNA—molecules that naturally regulate gene expression and give off different signatures in cancer cells versus healthy ones. The genetic circuit instructs the mRNA to self-destruct if it goes anywhere other than its intended target.
“We’ve engineered the mRNA so that they turn off if they go to someplace we don’t want them to be,” Becraft says.
Strand is initially targeting easy-to-reach tumors, including melanoma and breast cancer, to prove that the approach works and is safe. In this trial, doctors will inject the mRNA directly into the tumors and then check to see how localized the effect is. In the future, Strand envisions being able to do body-wide infusions of its programmed mRNA to treat tumors in more remote locations. The idea is that the therapy would selectively activate in certain cells and tissues.
Philip Santangelo, an mRNA researcher at the Winship Cancer Institute of Emory University, says there are benefits to Strand’s programmable approach even with injecting it at the site of a tumor. “If the drug goes outside the tumor when you inject it, then at least [its effect] will probably be restricted to the tumor,” he says.
IL-12 can be measured from the blood, so investigators will be able to take a blood draw and make sure the protein isn’t present there. Strand also plans to monitor various organs for the protein to see where it ends up. If the therapy works as intended, they shouldn’t find the protein anywhere outside the tumor.
But like computer circuits, genetic ones can occasionally make mistakes, says Ron Weiss, a professor of biological engineering at MIT who cofounded Strand and now acts as an adviser. “If your genetic circuit makes a mistake one out of 10 times, you do not want to use that as a therapy,” he says. “If it makes a mistake once every million times, that’s pretty good.”
Strand’s trial and other early attempts at these kinds of genetic circuits will see just how well they work. “The notion is that genetic circuits can really have a significant impact on safety and efficacy,” Weiss says.
Weiss pioneered the idea of genetic circuits, the first of which were based on DNA. When Becraft started graduate school in 2013, he joined Weiss’s lab to work on genetic circuits for mRNA. At the time, many scientists still doubted mRNA’s potential.
Now, Weiss imagines being able to use genetic circuits to program increasingly more sophisticated actions to create highly precise therapies. “This begins to really open up the door for creating therapies whose sophistication can match the underlying complexity of biology.”