mRNA technology could be possible treatment for rare genetic liver disease

Harnessing technology used in COVID-19 vaccines, a team led by scientists from UCL, King’s College London and Moderna has created an effective therapy for a rare disease, in a study on mice, demonstrating the potential therapeutic use of the technology in humans.

The research, published in Scientific translational medicinediscovered that messenger RNA (mRNA) could be used to correct a rare genetic liver disease known as argininosuccinic aciduria in a mouse model of the disease.

Argininosuccinic aciduria is an inherited metabolic disorder that affects how the body breaks down proteins, potentially leading to high levels of ammonia in the blood. Patients affected by the disease also have an imbalance in the regulation of glutathione, which is important for liver detoxification. This condition occurs in approximately one in 100,000 newborns.

Over the coming years, the team aims to test the therapy in humans. Messenger RNA therapies are also currently being studied in other rare inherited metabolic diseases – propionic and methylmalonic acidemias – in global clinical trials sponsored by Moderna, including at Great Ormond Street Hospital for Children.

Co-Principal Investigator Dr Julien Baruteau (UCL Great Ormond Street Institute of Child Health) said: “Messenger RNA has revolutionized the field of vaccines during the COVID-19 pandemic. We believe it can now do the same for rare diseases. “.

Rare diseases usually result from errors in the patient’s DNA and affect approximately 300 million people worldwide.

However, less than 5% of these conditions benefit from approved therapies. Most of these treatments use gene therapy to remove the defective gene and replace it with a normally functioning gene to relieve the disease.

Until recently, gene therapy used modified viruses to deliver the therapeutic gene to diseased cells. However, these viral systems can cause serious adverse effects, such as reactions from the patient’s immune system, meaning they cannot be deployed on a large scale.

Therefore, the team wanted to investigate the possibility of using mRNA technology as an alternative solution.

Messenger RNA is a molecule that contains instructions that tell cells to make proteins. By shielding the mRNA in a lipid microdroplet, the scientists were able to inject the therapy intravenously into the mice and target their liver cells.

The researchers tested the therapy on 31 mice from birth and at late stages of the disease as a rescue therapy in older mice with argininosuccinic aciduria. They also used an equal number of untreated mice as a control (comparison) group.

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

During the trial, mice underwent positron emission tomography (PET) scans as a non-invasive way to track correction of glutathione regulation and treatment success.

Researchers found that the treatment corrected the deadly consequences of the disease. All mice with the disease at birth and not treated died within the first two weeks of life, while mice given the mRNA treatment at birth survived for more than three months. Additionally, six out of seven mice given mRNA treatment as salvage therapy survived, while all of those left untreated died.

The researchers also noted that the mRNA-treated organs were very similar to those of unaffected control mice.

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

Dr Tim Witney, Co-Lead Researcher (School of Biomedical Engineering and Imaging Sciences, King’s College London), said: “This is an excellent example of collaborative science across multiple areas of expertise, which gave remarkable results. wrong in this disease, we can not only correct the error, but track this correction in real time using imaging. We look forward to bringing these advances to patients in the near future.

Dr. Paolo Martini, Scientific Director of Moderna’s International Therapeutics Research Centers, said: “This collaboration has illustrated how academia and industry can work in synergy to explore how mRNA technology can be harnessed against rare diseases and could potentially lead to treatment for these diseases. a serious and debilitating disease such as argininosuccinic aciduria.