Sixteen people have benefited from an experimental mRNA therapy that replaces a faulty enzyme behind a rare inherited condition, the biotech company Moderna announced on 19 May. This is great news for those with this condition, but its significance extends further: if this kind of mRNA therapy proves to be safe and effective, it could help treat a huge range of conditions and might even revolutionise medicine.
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| An illustration of messenger ribonucleic acid (mRNA) Kateryna Kon/Science Photo Library/Getty Images |
The people in the trial, aged 1 year and up, have a condition called propionic acidemia. This is caused by mutations in the gene for an enzyme that helps break down some components of proteins. When the enzyme is faulty, cells in the liver can’t do their job and toxic chemicals build up in the blood, damaging many organs, from the heart to the brain.
If untreated, the condition is usually fatal. But with treatment, including a tightly controlled diet, the prospects are much better. Even so, many still have episodes where toxins build up to dangerous levels, such as during infections. This causes vomiting and lethargy, and can lead to comas.
Moderna’s treatment consists of mRNAs, the templates cells use to make proteins, such as enzymes. The mRNAs are encased in fatty droplets to protect them while they are in the bloodstream. The droplets fuse with liver cells and release the mRNAs inside them. The cells then use the mRNAs to make working versions of the enzyme.
The principle is exactly the same as that of the mRNA covid-19 vaccines that millions of people have now received. However, in the case of the Moderna trial, the mRNAs are injected directly into the bloodstream so they can reach the liver, and bigger doses are required. Because mRNAs don’t persist in cells, the trial participants were given injections every two weeks.
Five of the 16 people have been receiving the treatment for more than a year and the therapy is “well-tolerated”, according to Moderna. Those receiving it have had fewer or no episodes caused by a toxin buildup, it says.
“This is the first clinical trial reporting results of an mRNA therapeutic for intracellular protein replacement,” Kyle Holen of Moderna said in a statement.
Why is this news exciting for the entire field of medicine, not just those with this condition? At the moment, most drugs are small molecules. They have the advantages of being cheap to make – if not necessarily to buy – and being able to diffuse through the gut into the bloodstream and then through the cell membrane into cells.
The disadvantage of their small size is that they don’t bind precisely to their targets, often attaching to non-target sites as well – like a tiny jigsaw puzzle piece that can fit in lots of places it doesn’t belong. This is why they often have lots of side effects.
Large molecules such as proteins are much more precise and powerful than small molecules, but proteins are difficult to manufacture. They also can’t get through the gut wall and can’t get from the blood into cells. Injecting proteins gets around the issue of passing through the gut wall, but does not solve the other two issues.
There are a growing number of protein-based drugs, mostly artificial antibodies designed to treat infections or cancers. Many are extremely effective – but they are also extremely expensive and their uses are limited, as none gets inside cells. mRNAs could solve these issues too, as they are cheap to make compared with proteins and this Moderna trial shows you can use them to effectively get proteins inside cells.
That said, there were a lot of adverse events in the trial, says Anna Blakney at the University of British Columbia, Canada, suggesting the dosage was at the limits of what is safe.
It is also relatively easy to deliver mRNAs to liver cells because the liver mops up anything added to the blood. To treat many conditions, mRNAs will need to be delivered to other cell types, which remains a challenge.
So, there is still a long way to go before mRNA shots are used to treat a range of conditions, but given that many pioneering treatments fail altogether, this is an excellent start. “It’s definitely promising and a step forward for the field,” says Blakney.
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