New mRNA therapy shows promise in treating 'ultrarare' inherited disease

A new treatment may be able to treat a life-threatening disorder that predominantly affects children, initial findings from a pioneering clinical trial suggest.

The disorder, called propionic acidemia (PA), is an inherited metabolic disorder that affects around 1 in 100,000 people in the U.S. Individuals with the disease have faulty copies of genes needed to make parts of the enzyme propionyl-coenzyme A carboxylase (PCC), which breaks down the building blocks of certain proteins and fats. 

Without fully functional PCC enzymes, harmful compounds accumulate in the body, triggering recurrent symptoms known as "metabolic decompensation events" (MDE). These episodes include lethargy, vomiting, dehydration, and in serious cases, potentially coma and death. In most instances, symptoms of this rare disorder become apparent a few days after birth. 

There is currently no cure for PA. Instead, treatments aim to manage the symptoms of the disease, by getting patients to follow a carefully controlled, low-protein diet, for example, and frequently replacing lost fluids to prevent dehydration. Patients may also require liver transplants, as replacing this key organ involved in metabolism can help somewhat restore their levels of functioning PCC.

But now, scientists are testing a new therapy for PA that uses messenger RNA (mRNA) — a genetic molecule that contains the instructions cells need to make proteins. The same type of molecule serves as the basis of the COVID-19 vaccines made by Pfizer and Moderna. The new treatment, called mRNA-3927, contains mRNA needed to make the two subunits of PCC that are faulty in patients with PA, thus helping to replenish stocks of working enzymes in the body. 

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In the recent trial, described Wednesday (April 3) in the journal Nature, scientists enrolled 16 patients with PA, whose ages ranged from 1 to 28. Twelve participants completed this interim analysis.