Moderna Therapeutics is betting that messenger RNA can turn cells into factories for missing proteins.

V. Altounian/Science

Can a multibillion-dollar biotech prove its RNA drugs are safe for a rare disease?

Earlier this year, Paolo Martini, who heads rare disease research at the closely scrutinized biotech company Moderna Therapeutics in Cambridge, Massachusetts, visited the Middle East. He met with doctors who treat children with a rare metabolic disorder known as methylmalonic acidemia—more prevalent in the region than most places because of the custom of marrying close relatives—that causes a toxic acid to build up in their blood. Soon, his team hopes to start enrolling these children in a pioneering clinical trial that delivers “messenger RNAs”—the molecules that normally carry instructions from a cell’s DNA to its proteinmaking machinery. But Moderna, which has raised billions of dollars on the promise of treating a wide range of diseases with such RNA, first has to prove that its drugs are safe for long-term use.

In a study published online today in Cell Reports, the company shows that there were no obvious health problems in mice given repeated doses of its latest generation of messenger RNA (mRNA) drugs. The finding is far from definitive evidence of safety, but it’s some of the first published animal research supporting the use of this type of RNA as long-term therapy in diseases like methylmalonic acidemia (MMA). “It’s good news for the mRNA delivery field and an important step,” says Kathryn Whitehead, a chemical engineer at Carnegie Mellon University in Pittsburgh, Pennsylvania, who was not involved in the study.

MRNA excites scientists because its powers are broad. If you can put new mRNA into a cell, you can theoretically tell it to make any protein. Missing an enzyme that helps break down food? Send in mRNA to resupply it. Need to heal tissue around a damaged heart? Inject mRNA coding for a growth-promoting protein. “I don’t know if I’ve ever been more excited about a class of drug than I am about [mRNA],” Whitehead says.

But lots can go wrong when you try to sneak such molecules into the body. Our immune system has evolved to recognize RNA from outside the cell as an invading virus and attack it. The protective nanoparticles made of lipids commonly used to encapsulate mRNA can also trigger immune reactions and damage the liver at high doses. And the body might even recognize the newly produced protein as foreign—a problem if you’re trying to replace a vital protein that’s missing. Any of those responses could render an mRNA drug toxic at doses still too low to treat disease.

Six-year-old Moderna has promised to engineer its way out of those traps. Researchers there have altered the chemistry of the mRNA itself so it doesn’t set off receptors on roving immune cells. The company has begun human testing of its mRNA drugs for cardiovascular disease and cancer, and for vaccines against the flu, Zika, and chikungunya viruses. And it’s not alone. Germany-based biotech companies CureVac and BioNTech are also testing several mRNA-based cancer vaccines in clinical trials.

But those drugs are designed to work in just one or a few doses. To treat genetic diseases where a key protein is absent or defective, companies will need an mRNA drug that’s safe and effective for repeated use throughout a patient’s life. Some have been skeptical that’s achievable. Early generations of Moderna’s drugs didn’t meet that standard in animal tests, acknowledges its president, Stephen Hoge; over time, liver toxicity and immune reactions reared their heads.

But Moderna’s newer drugs don’t have those problems, he says, thanks in part to a careful redesign of their delivery vehicle, the lipid nanoparticle. A key innovation—to be described in another forthcoming paper—is that the nanoparticle quickly sheds one of its key lipid components upon entering the body, rendering it stealthier and less toxic.

In the new study, Moderna worked with scientists at the National Institutes of Health in Bethesda, Maryland, to test how effectively that new nanoparticle delivers mRNA encoding the protein that’s missing or defective in MMA patients. The enzyme, known as methylmalonyl-CoA mutase (MUT), is made primarily in the liver, and it helps break down proteins and fats in food. Without it, the buildup of methylmalonic acid in the blood can cause weakness and slowed development, kidney and liver damage, and even seizures and stroke. Children diagnosed with MMA must eat a restrictive diet, and some undergo liver transplants.

In Moderna’s study, the researchers gave intravenous injections of MUT-encoding mRNA to mice lacking the enzyme. The treatment reduced blood levels of toxic acid by up to 85%, they revealed today. After getting weekly injections for 5 weeks, the mice did not have elevated levels of liver enzymes that signal toxicity, and there was no increase in certain markers of inflammation, or in antibodies that indicate an immune response.

“We saw these mice not only surviving but gaining weight, turning almost into a normal mouse,” Martini says. “These data I think [are] the validation, at least in animal models, that this messenger RNA therapy could work.”

Other researchers want to see much more evidence of long-term safety. “This is a good first step,” says geneticist Inder Verma of the Salk Institute for Biological Studies in San Diego, California. He would have liked to see the mice followed for longer and given even higher doses, he says. In a study published earlier this year, his team, along with scientists at Arcturus Therapeutics, treated hemophilia in mice using mRNA that encodes a clotting protein. The drug, administered in three doses over 5 months, did prompt temporary spikes in certain inflammatory molecules, which indicate a mild immune reaction to the drug. “I don’t think our paper or this paper adequately addresses the issue of long-term toxicity due to the immune system,” Verma says.

To please regulators that would ultimately greenlight clinical trials, Moderna will have to show its drug is still safe at a dose 10 times higher than what’s needed to treat the disease—something the new paper doesn’t demonstrate, says geneticist Michael Heartlein, chief technical officer at the competing mRNA company Translate Bio in Cambridge. “That’s what I’d like to see, to really nail it and say, ‘Hey, they’ve really got something that’s viable for the clinic.’” (Translate is planning human trials with repeated doses of its own mRNA drug for both cystic fibrosis and a rare metabolic disorder called ornithine transcarbamylase deficiency in 2018, but it has not yet published animal studies with repeat dosing.)

Hoge says he’s already confident the drug’s safety can exceed that factor-of-10 standard. These mice have been followed for several more weeks with no signs of toxicity, and Moderna has similar results from nonhuman primate studies that they plan to publish soon, he says. Martini notes that his Middle East trip has doctors there anxiously watching for a possible new drug. “Seeing the hope in the eyes of these physicians … of potentially having something to test was incredible.”