Study reveals therapeutic potential of mRNA in rare diseases


Researchers have used messenger RNA (mRNA) to create an effective therapy for a rare liver disease in preclinical studies, demonstrating the technology’s potential therapeutic use in people.

The team, led by University College London (UCL), King’s College London and Moderna scientists, found that mRNA could be used to correct a rare genetic liver disease known as argininosuccinic aciduria in a mouse model.

Argininosuccinic aciduria is an inherited metabolic disorder that affects how the body breaks down protein – potentially leading to high levels of ammonia in the blood. Patients affected by the disease are found to also experience an imbalance of glutathione regulation, which is important for liver detoxification.

Messenger RNA therapies are also currently being investigated in other rare inherited metabolic diseases – propionic and methylmalonic acidaemias – in global clinical trials sponsored by Moderna, including at Great Ormond Street Hospital for Children.

Co-lead Principal Investigator, Dr Julien Baruteau (UCL Great Ormond Street Institute of Child Health), said: “mRNA has revolutionised the field of vaccines during the Covid-19 pandemic. We believe it can now do the same for rare diseases.”

Successful industry/academia collaboration

Fewer than 5% of rare diseases have approved therapies and most of these treatments use gene therapy.

Until recently, gene therapy employed modified viruses to bring the therapeutic gene to the disease cells, but these viral systems can cause severe adverse effects.

mRNA contains instructions that direct the cells to make proteins. By protecting the mRNA in a microdroplet of lipids, scientists were able to inject the mice intravenously with the therapy and target their liver cells.

For the mice, the benefit of each mRNA treatment only lasted around seven days, so the procedure was performed weekly over the course of up to eight weeks. However, the researchers expect that translation to humans will allow for longer gaps between treatments.

Researchers found that all mice with the disease at birth left untreated died within the first two weeks of life, while the mice that received the mRNA treatment at birth survived for over three months. The researchers also noted that, mRNA-treated organs were very similar to those in the unaffected, control mice.

Dr Baruteau said: “We have shown that mRNA holds an unprecedented therapeutic potential for incurable genetic diseases, in particular liver conditions. We aim to apply this approach to other inherited liver diseases and translate mRNA therapy to patients, especially in children.”

Dr Paolo Martini, Chief Scientific Officer for International Therapeutics Research Centres at Moderna, added: “This collaboration has exemplified how academia and industry can work in synergy to explore how mRNA technology can be harnessed against rare diseases and may potentially lead to a treatment for a severe and debilitating disease such as argininosuccinic aciduria.”

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