Hope for rare anemia patients: Czech scientists create "perfect" mouse model

A team of Czech researchers has achieved a breakthrough in understanding Diamond-Blackfan Anaemia (DBA), a rare and severe genetic disease that cause anemia and inborn malformations in children. By creating a unique mouse model that perfectly mimics the pathologic condition, scientists from the Czech Centre for Phenogenomics (Institute of Molecular Genetics of the Czech Academy of Sciences) and the First Faculty of Medicine, Charles University (BIOCEV) have opened the door to safer, more effective treatments. Their findings were recently published in the prestigious medical journal HemaSphere.

The Mystery of the "Broken Factories". DBA is caused by a glitch in the body’s ability to assemble and utilize ribosomes, the microscopic "factories" inside our cells that produce proteins. When these factories malfunction, the body stops producing red blood cells, leading to severe anemia. Many patients also suffer from physical defects, such as heart and other organ malformations or stunted growth. Until now, scientists struggled to study this disease because they couldn't replicate it in the lab. Previous attempts to create mice with this genetic defect failed because the animals would die before birth, making it impossible to test potential cures.

A "Goldilocks" Solution. The teams of Tomáš Stopka and Radislav Sedláček used advanced gene-editing tools to make a tiny, precise tweak to the mouse’s DNA. Instead of breaking the gene completely, they deleted just a tiny fraction of it, mimicking the exact genetic situation found in human patients. "We essentially created a 'Goldilocks' model," explains Radislav Sedláček, Director of the Czech Centre for Phenogenomics. "The genetic change wasn't severe enough to be lethal, but it was significant enough to cause the disease. Just like human patients, some of our mice have severe symptoms while others are milder. This gives us the perfect real-world scenario to test new drugs." Tomáš Stopka adds: "It is highly interesting that in a precisely genetically determined model, the DBA phenotype is highly variable, which shows that the organism is able to cope with the mutation to a greater or lesser extent in some individuals."

Pulling the Emergency Brake Too Early. Using this new model, the team discovered why the red blood cells vanish. They found that when the cell’s protein factories (ribosomes) are under stress, a "guardian" protein called p53 panics and pulls the cellular emergency brake. The researchers discovered this happens much earlier than previously thought, affecting the "grandparent" stem cells in the bone marrow before they even have a chance to become red blood cells. The collaboration between the two teams draws on expertise in cutting-edge mouse transgenics and molecular and cellular hematology, which has created synergies. Without the support of grants from, for example, the Czech Science Foundation or the NextGenerationEU, we would not have been able to do this.

New Targets for Treatment. The team proved that if they turned off the p53 "emergency brake," the anemia was cured. However, p53 is also essential for preventing cancer, so turning it off entirely isn't a safe option for humans. But there is good news. The study identified several specific molecules that work for p53. These molecules are like wires connected to the brake. "We have identified specific 'worker' molecules that actually stop the blood cell production," says lead author Juraj Kokavec. "This is exciting because it gives us a target. If we can develop drugs to block these specific molecules, we might be able to treat the anemia, possibly also from other causes, without disabling the body's entire cancer-defense system."

About the Study

• Journal: HemaSphere
• Title: Rps19^R67∆ mutation creates a model of Diamond-Blackfan anaemia and reveals downstream mediators of p53 pathway.
• Link: https://onlinelibrary.wiley.com/journal/25729241

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