Scientists to test anti-cancer mRNA treatment

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To keep IL-12 inside the tumor, Strand scientists designed a set of instructions, called a genetic circuit, that tells the mRNA to make inflammatory proteins only when it detects the tumor microenvironment . The circuit is designed to understand the levels of microRNAs—molecules that naturally regulate gene expression and yield different signatures in cancer cells versus healthy cells. The genetic circuit instructs the mRNA to destroy itself if it goes anywhere other than its intended target.

“We've engineered the mRNAs so that if they go somewhere we don't want them to go, they're turned off,” says Becroft.

Strand is initially targeting easier-to-reach tumors, including melanoma and breast cancer, to prove that the approach works and is safe. In this trial, doctors will inject mRNA directly into the tumor and then check how local the effect is. In the future, Strand envisions being able to perform body-wide infusions of his programmed mRNA to treat tumors in more remote locations. The idea is that the therapy will be selectively active in certain cells and tissues.

mRNA researcher Philip Santangelo of Emory University's Winship Cancer Institute says Strand's programmable approach also has advantages over injecting it into the tumor site. “If the drug moves outside the tumor when injected, at least [its effect] Will probably be confined to the tumor,” he says.

IL-12 can be measured from blood, so investigators can take a blood sample and make sure the protein is not present there. Strand also plans to monitor different organs for the protein to see where it ends up. If the therapy works as intended, they should not find the protein anywhere outside the tumor.

But like computer circuits, genetic circuits can sometimes make mistakes, says Ron Weiss, a professor of biological engineering at MIT, who co-founded Strand and now serves as an adviser. “If your genetic circuitry makes a mistake one time out of 10, you don't want to use that as a therapy,” he says. “If it makes a mistake once every million times, that's great.”

Strand's tests and other early efforts on these types of genetic circuits will reveal how well they work. “The hypothesis is that genetic circuits can really have a significant impact on safety and efficacy,” says Weiss.

Weiss pioneered the idea of ​​genetic circuits, the first of which was based on DNA. When Beecroft started graduate school in 2013, he joined Weiss's lab to work on genetic circuits for mRNAs. At the time, many scientists were still skeptical of the potential of mRNA.

Now, Weiss envisions being able to use genetic circuits to program more sophisticated actions to create highly precise treatments. “This really begins to open the door to creating treatments whose sophistication can match the inherent complexity of the biology.”