Messenger RNA technology shows first promise against a rare and deadly disease

The innovative technology behind some of the most successful COVID-19 vaccines is showing signs of success in treating a rare but dangerous metabolic disease. Researchers report today in Nature that regular infusions of messenger RNA (mRNA) coding for a missing enzyme may have slashed the rate of life-threatening medical emergencies in a handful of people with propionic acidemia, a condition in which toxic compounds build up in the body and damage organs.

The results from Moderna are the first published clinical data showing that mRNA, used in vaccines to deliver viral proteins that provoke an immune response, could potentially work as a drug to replace a protein people lack. And although the data only hint that patients’ health improved, they “are very, very encouraging,” says metabolic disease specialist Gerard Vockley of the University of Pittsburgh, who helped design the trial but was not involved in treating patients.

Although mRNA vaccines for COVID-19 were a breakthrough and earned two of their developers a Nobel Prize, Moderna and others have much wider ambitions for the proteinmaking technology. Moderna is testing mRNA encoding tumor proteins that prompt the immune system to attack tumors, essentially a cancer vaccine. Other companies are reporting success at using mRNA to deliver the gene editor CRISPR into a patient’s cells to disable a problematic gene . But before the COVID-19 pandemic, one of Moderna’s big goals was to use mRNA to treat people who are sick because they carry mutations that lead to missing or defective proteins.

One such disease is propionic acidemia, caused by mutations in genes encoding one of two subunits of an enzyme that helps mitochondria, cells’ powerhouses, break down certain amino acids and fats. When the enzyme doesn’t work properly in the liver, ammonia and other toxic compounds released into the blood accumulate in organs and can cause problems such as coma, strokes, seizures, and heart disease. Although children diagnosed with the disease usually get a special diet that lacks the problematic amino acids, most still have serious health issues.

Doctors can’t simply infuse the needed enzyme into patients’ blood because it has trouble getting from there into liver cells and their mitochondria. Patients with more severe disease sometimes get a transplant of a healthy liver that produces normal enzyme. But the transplants are risky and require lifelong immunosuppressive drugs.

Moderna’s approach is to infuse the blood with tiny fat particles containing two mRNAs encoding both parts of the missing enzyme. These naturally travel to the liver, where cells use the mRNAs as templates to make these components and assemble the functioning enzyme. In the trial, 16 children and young adults with the disease got intravenous infusions of these mRNA-packed lipid nanoparticles at one of five doses, usually 2 weeks apart.

The infusions caused side effects such as nausea, vomiting, and fever, and some participants had an allergic reaction. But all 12 who stayed in the study have been able to continue treatment for as long as 2 years. And in eight who had at least one disease-related life-threatening emergency in the year before treatment, such episodes fell by 70% , Moderna and its academic collaborators report in the Nature paper. That, along with a trend toward lower blood levels of some disease-related metabolites, offers “a hint that some enzyme is being made” by the liver, says clinical geneticist and metabolic disease specialist Dwight Koeberl of Duke University, first author on the paper. (More direct proof would have required an invasive liver biopsy.)

The decline in emergencies “is hugely important for these patients and families,” says Stephanie Grünewald, a consultant in metabolic medicine at the Great Ormond Street Hospital for Children who treated several of the patients and is corresponding author on the paper. “What is most exciting for me is that there are so many metabolic disorders in this group that shout out to be treated in this same way,” she adds. (Moderna is running a trial for another such disorder, methylmalonic acidemia.)

Physician-scientist Charles Venditti of the National Human Genome Research Institute notes that various mutations can cause propionic acidemia, and he would have liked the study authors to describe the specific mutations participants carried. If some had the type that results in no enzyme at all, their improvement could have masked minimal gains in other patients with some functioning enzyme. “There’s a signal for efficacy, but it's not convincing because there’s no details provided,” says Vendetti, who is working on a gene therapy for propionic acidemia that could insert a new gene into patients’ cells and provide a potentially more permanent fix.

Still, others find Moderna’s first paper on a rare disease trial compelling. Although the biweekly infusions are burdensome, they could help young patients stay healthy until receiving a liver transplant or gene therapy, Vockley says.

The study also offer reassurance that long-term, repeated doses of mRNA-containing lipid nanoparticles—much higher than in vaccines—won’t cause an immune reaction that makes them unsafe or erodes their benefits over time, says pharmaceutical scientist Gaurav Sahay of Oregon State University. “This is a really important milestone for the field.”