Summary: Rapamycin could counteract the harmful effects of Sodium Valproate, a common epilepsy medication, on fetal spinal cord development. Sodium Valproate is widely prescribed but poses risks during pregnancy, causing spinal malformations in fetuses.
Using organoids (human mini-spinal cords), researchers identified how the drug causes malformations and found that co-treatment with Rapamycin prevents these effects. This breakthrough could help women with epilepsy safely continue their medication during pregnancy.
Key Facts:
- Sodium Valproate can cause spinal defects in fetuses when used during pregnancy.
- Researchers used organoids to study and prevent these harmful effects.
- Co-treatment with Rapamycin may allow safer use of the epilepsy drug for pregnant women.
Source: University of Queensland
University of Queensland researchers have made a significant step towards enabling women with epilepsy safer access to a common and highly effective anti-seizure medication.
Sodium Valproate or valproic acid is widely prescribed for epilepsy and certain mental health conditions, but is considered harmful to use during pregnancy because of links to spinal cord defects and other complications for newborns.
Dr Giovanni Pietrogrande and Professor Ernst Wolvetang from UQ’s Australian Institute for Bioengineering and Nanotechnology (AIBN) led a team of organoid experts who have identified a drug that could nullify the dangerous side effects.
“We first set out to understand why valproate causes spinal cord malformations in fetuses,” Dr Pietrogrande said.
“To do this we created organoids – human mini-spinal cords in a dish – that closely mimic the spinal cord of a fetus in the early weeks of gestation.
“When these mini spinal cords were exposed to valproate, the team discovered that the drug changes the cells that normally form the spinal cord, leading to malformations.”
Professor Wolvetang said the AIBN team then treated the organoids with the clinically approved drug Rapamycin, and found it prevented the negative effects of valproic acid.
“Therefore co-treatment with Rapamycin could be the thing that opens safe access to an extremely effective treatment for women with epilepsy,” Professor Wolvetang said.
Study co-author Professor Terence O’Brien, Head of the School of Translational Medicine at Monash University and program director and deputy director of research at Alfred Brain, said the findings could help healthcare providers and patients navigate the complex challenges around the treatment of epilepsy.
“It may also provide a pathway to enabling women to continue to take this life saving medication while having healthy children,” Professor O’Brien said.
Professor Wolvetang said the research highlights the potential of new technologies like human stem cell derived organoids to explore the molecular and cellular impacts of drugs.
“Organoids are a tool that allow us to develop new treatments, and also to uncover new ways to improve the safety and efficacy of existing ones,” he said.
“We hope this research is another step towards fostering regulatory change in the Therapeutic Goods Administration (TGA) to establish organoids as a powerful tool for drug screening and discovery.”
The work was conducted in partnership with AIBN colleagues Dr Mohammad Shaker, Dr Julio Aguado, Dr Ibrahim Javed, Professor Tom Davis, Tahmina Tabassum and Sean Morrison, as well as collaborators from UQ’s School of Chemical Engineering, The University of Melbourne and Vita-Salute San Raffaele University in Milan.
About this neuropharmacology research news
Author: Alex Druce
Source: University of Queensland
Contact: Alex Druce – University of Queensland
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models” by Giovanni Pietrogrande et al. Molecular Psychiatry
Abstract
Valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models
Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear.
Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube.
We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs.
We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach.
Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention.
These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery.
