To keep IL-12 in tumors, Strand scientists 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 microRNAs, molecules that naturally regulate gene expression and emit different characteristics in cancer cells and healthy cells. Genetic circuits instruct mRNA to self-destruct when it reaches a location other than its intended target.
“We engineered the mRNA in such a way that it was turned off when it went somewhere we didn’t want it to go,” Beecraft says.
Strand will initially target easier-to-reach tumors, such as melanoma and breast cancer, to prove the approach is effective and safe. In this trial, doctors inject mRNA directly into tumors to see how local the effects are. In the future, Strand envisions that programmed mRNA could be injected throughout the body to treat tumors in more distant locations. The idea behind this treatment is to selectively activate specific cells and tissues.
Philip Santangelo, an mRNA researcher at Emory University’s Winship Cancer Institute, said Strand’s programmable approach also has advantages when injected at tumor sites. “If the drug gets out of the tumor at the time of injection, at least [its effect] “It’s probably limited to tumors,” he says.
IL-12 can be measured in blood, so researchers could draw blood to confirm that the protein is not present. Strand also plans to monitor different organs to see where the proteins end up. If the treatment is working as intended, the protein should not be found outside the tumor.
But like computer circuits, genetic circuits can sometimes make mistakes, says Ron Weiss, a bioengineering professor at the Massachusetts Institute of Technology who co-founded and now serves as an advisor to Strand. “Even if a genetic circuit makes one mistake in 10, you don’t want to use it as a treatment,” he says. “If he makes one mistake in a million, that’s pretty good.”
Strand’s trials and other early attempts at genetic circuits of this kind will tell us how well they work. “The idea is that genetic circuits can actually 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 Beecraft entered graduate school in his 2013 year, he joined Weiss’s lab and worked on studying mRNA genetic circuits. At that time, many scientists still had doubts about the potential of mRNA.
Now, Weiss envisions genetic circuits being able to be used to program increasingly sophisticated behaviors and create highly precise treatments. “This really starts to open the door for developing advanced treatments that match the underlying complexity of biology.”