June 23, 2024

mRNA Technology Shows Promise as Treatment for Rare Liver Genetic Disease

Scientists from UCL, King’s College London, and Moderna have made a significant breakthrough in the treatment of a rare liver genetic disease by harnessing the technology used in COVID-19 vaccines. In a study conducted on mice, the researchers demonstrated the potential therapeutic use of messenger RNA (mRNA) in correcting a metabolic disorder known as argininosuccinic aciduria.

Argininosuccinic aciduria is an inherited condition that affects the body’s ability to break down protein, leading to increased levels of ammonia in the blood. Patients with this disease also experience an imbalance in glutathione regulation, which is crucial for liver detoxification. The condition is rare, occurring in approximately one in 100,000 newborns.

The research, published in Science Translational Medicine, showed that mRNA could be used to correct the genetic defect associated with argininosuccinic aciduria in a mouse model. The team’s goal is to further explore the therapy in human trials in the coming years. Additionally, Moderna is sponsoring global clinical trials investigating mRNA therapies for other rare metabolic diseases, such as propionic and methylmalonic acidemias, including at Great Ormond Street Hospital for Children.

Dr. Julien Baruteau, co-lead principal investigator at UCL Great Ormond Street Institute of Child Health, stated that mRNA has the potential to revolutionize the treatment of rare diseases, just as it has transformed the field of vaccines during the COVID-19 pandemic.

Rare diseases, which result from genetic errors, affect approximately 300 million people worldwide. However, only a small percentage of these conditions have approved therapies. Most treatments involve gene therapy, which aims to replace the faulty gene with a healthy one to alleviate the disease.

Traditionally, gene therapy relied on modified viruses to deliver the therapeutic gene to the affected cells. However, these viral systems can cause severe adverse effects due to immune reactions, limiting their widespread use. To overcome this challenge, the researchers explored the possibility of using mRNA technology as an alternative solution.

Messenger RNA carries instructions that direct cells to produce proteins. By encapsulating the mRNA in lipid microdroplets, the scientists were able to deliver the therapy directly to the liver cells in the mice via intravenous injection.

The researchers tested the therapy on mice with argininosuccinic aciduria, both from birth and at a later stage of the disease as a rescue therapy. They compared the results to a control group of untreated mice. Each mRNA treatment provided benefits for only about seven days, so the procedure was repeated weekly for up to eight weeks. However, the researchers anticipate that longer gaps between treatments will be possible in humans.

Throughout the trial, the mice underwent positron emission tomography (PET) scans to track the correction of glutathione regulation and assess the success of the treatment. The results showed that the mRNA treatment corrected the lethal consequences of the disease. All untreated mice with the disease from birth died within two weeks, while those receiving the mRNA treatment at birth survived for over three months. Among the mice treated with mRNA as a rescue therapy, six out of seven survived, while all untreated mice died.

Furthermore, the researchers observed that the mRNA-treated organs closely resembled those of the unaffected control mice.

Dr. Baruteau expressed optimism about the potential of mRNA therapy for incurable genetic diseases, particularly liver conditions. The team plans to apply this approach to other inherited liver diseases and translate mRNA therapy to patients, especially children.

Dr. Tim Witney, co-lead principal investigator at the School of Biomedical Engineering & Imaging Sciences, King’s College London, highlighted the collaborative nature of the research and its ability to yield significant results. By understanding the nature of the disease and correcting the underlying genetic error, the researchers aim to bring these advancements to patients in the near future.

Dr. Paolo Martini, Chief Scientific Officer for International Therapeutics Research Centers at Moderna, emphasized the importance of collaboration between academia and industry in exploring the potential of mRNA technology in treating rare diseases. The success of this collaboration offers hope for finding a treatment for severe and debilitating conditions like argininosuccinic aciduria.

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Source: Coherent Market Insights, Public sources, Desk research
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