An international research team from Mannheim, Göttingen, Varna, and Princeton, with participation from MU–Varna, has demonstrated that the growth factor recombinant human erythropoietin (rhEPO) can significantly improve cognitive and social impairments in Primrose syndrome—a rare and severe genetic disorder caused by reduced levels of the ZBTB20 gene. The results were published in the prestigious scientific journal Journal of Clinical Investigation Insight, and provide the first evidence that erythropoietin may counteract a severe neurodevelopmental condition. The scientific article entitled “Erythropoietin alleviates syndrome-associated intellectual disability and autism-like behaviour in Zbtb20-haploinsufficient Primrose syndrome mouse model" is available here.
Primrose syndrome is an extremely rare inherited disorder associated with severe cognitive impairment and intellectual disability, serious social and behavioural difficulties, and a range of physical abnormalities, including skeletal and facial changes. The condition is caused by mutations in the ZBTB20 gene—a key regulatory gene that controls brain development and function. Genetic variants of ZBTB20 are also found in patients with autism spectrum disorders, which are much more common and have significant societal impact.
Erythropoietin is best known as a hormone that stimulates the production of red blood cells and has long been used to treat anaemia. Less well known is that the brain has its own erythropoietin receptors on neurons, glial cells, and blood vessels, and some brain cells can even produce it themselves, especially under stress, low oxygen levels, or inflammation. When erythropoietin binds to these receptors, it triggers complex intracellular signalling pathways that protect nerve cells from dying, stimulate the formation and maturation of new neurons, improve connectivity between them, reduce inflammation and oxidative stress, and support cerebral blood flow. This complex “brain" effect is believed to underpin the improvement in cognitive and social functions observed in experiments.
In an animal model of Primrose syndrome—transgenic mice with reduced levels of the ZBTB20 gene—the researchers found that administration of recombinant human erythropoietin led to significant improvements in learning and memory capabilities, better social behaviour, and reduced behavioural abnormalities. In addition, the therapy partially normalised some of the disrupted brain processes underlying the disorder. This is the first evidence that an already approved and well-known drug can correct severe neurological deficits caused by a genetic defect such as ZBTB20.
At this stage, the results are preclinical and were obtained in animal models, not in humans. Erythropoietin is not yet an established treatment for Primrose syndrome in patients, and further studies are required to evaluate safety, determine optimal dosing, and conduct controlled clinical trials. Nevertheless, the discovery is highly encouraging, as it involves a drug already used in clinical practice for other indications, with substantial accumulated experience.
According to Prof. Hannelore Ehrenreich from Mannheim, the lead researcher of the team: “The remarkable effect of erythropoietin is mediated through a direct influence on the levels of the ZBTB20 gene." The contribution of two Bulgarian scientists—Prof. Anton Tonchev from MU–Varna and Prof. Anastasia Stoykova from the Max Planck Institute in Göttingen—was key in establishing the ZBTB20 gene reduction model as a model for neurodevelopmental disorders. According to Prof. Tonchev: “The availability of this mouse model in Bulgaria will enable testing of future therapeutic approaches not only for the rare Primrose syndrome but also for the much more common autism spectrum disorders."
News about the discovery has been published on the website of the Central Institute of Mental Health at the Medical Faculty Mannheim. You can read the publication here.
The work on the article was co-funded by the Scientific Group “NutriLect" under NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project No. BG-RRP-2.004-0009 “Medical University – Varna: Enhancement of Translational Excellence Achievement in Medicine (MUVE-TEAM)".
Velina Markovska
