Lipid nanoparticles deliver mRNA (blue) to liver cells to produce specific enzymes./V. Altounian, Science
There is a high possibility that messenger ribonucleic acid (mRNA), developed as a vaccine for the new coronavirus (COVID-19) and which won the Nobel Prize last year, could be developed as a treatment for rare metabolic diseases.
A joint research team including the American biotechnology company Moderna, Great Ormond Street Children’s Hospital in the United Kingdom and Duke University in the United States announced on Thursday the results of a Phase 1 and 2 clinical trial that showed that the symptoms of propionic acidemia can be eliminated and reduced by injecting specific mRNA to remove toxic substances accumulated in the body (local time) It was published in the international academic journal “Nature”. This therapeutic drug, like the mRNA COVID-19 vaccine developed by Pfizer and Moderna in the United States, is loaded with mRNA, a therapeutic agent, onto lipid nanoparticles and injected into the blood.
Propionic acidemia is a metabolic disease in which an enzyme called propionyl coenzyme A carboxylase α or β (PCCA or PCCB) is not produced due to a mutation, resulting in the inability to break down certain proteins such as propionic acid and glycine. If these proteins are not properly broken down in the liver, ammonia builds up in the organ and causes toxicity. Newborns may experience vomiting and loss of appetite, but this can gradually lead to strokes, seizures, heart disease and brain damage, resulting in loss of life. It affects around 1 in 100,000 people and there is still no cure. Therefore, children diagnosed with propionic acidemia must follow a special diet for the rest of their lives that excludes problematic amino acids.
Moderna researchers noted that the treatment cannot be done simply by injecting the patient’s needed enzymes into the blood. To treat propionic acidemia, enzymes must enter the liver cells, which is almost impossible. So researchers focused on the principles of the mRNA COVID-19 vaccine. The COVID-19 mRNA vaccine contains the COVID-19 virus spike protein gene mRNA in lipid nanoparticles. When this vaccine enters the body, the immune system creates immunity against the virus. In the future, when a real virus invades, we will be able to respond immediately. In this way, mRNA-3927 developed by Moderna is a lipid nanoparticle loaded with mRNA for PCCA and PCCB. When this drug travels through the bloodstream to the liver, liver cells produce the necessary enzymes based on the mRNA in it.
In a clinical study, researchers injected mRNA-3927 intravenously at 2-3 week intervals for 2 years to 16 children with propionic acidemia. As a result, 8 patients experienced a 70% reduction in life-threatening emergencies compared to before treatment. turns out. The researchers analyzed that mRNA treatments could be used as a way to maintain the health of child patients until they become adults and receive liver transplants or gene therapy.
Dwight Koeberl, a professor of pediatrics at Duke University School of Medicine who participated in the study, explained that day in the international academic journal Science: “Blood levels of the metabolites that cause propionic acidemia, such as ammonia, are decreased.” , adding: “This means that the necessary enzymes are produced in the liver.”
So far, mRNA is limited to vaccines, not therapeutic drugs, in clinical trials. These findings are the first clinical results showing the potential of mRNA to act as a drug to replace proteins that people lack. It is also the basis for revealing that even if the mRNA is administered repeatedly over a long period of time, no side effects occur or the effectiveness of the drug decreases.
Corresponding author Stephanie Grünewald, a consultant in metabolic medicine at Great Ormond Street Children’s Hospital, said: “There are many diseases other than propionic acidemia that cause organ damage due to the absence of specific enzymes” and have explained: “They could be treated similarly.” Researchers are also conducting clinical trials in methylmalonic acidemia, a similar metabolic disease. This disease is caused by poor metabolism of vitamin B12 due to a genetic mutation, which causes a buildup of toxicity in the body.
Additionally, researchers at biotech companies and universities, such as Moderna, are researching and developing cancer vaccines that attack tumors using mRNA and gene therapy drugs that deliver CRISPR genetic scissors into the body to knock out specific genes.
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