Unique Model of Rare Epileptic Disease Helps Pinpoint Potential Treatment Route
The study was supported by a CURE Epilepsy Award from CURE Epilepsy that was co-funded by Raiden Science Foundation; and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
While extremely rare, encephalopathy (a condition affecting brain function) triggered by mutations in the UBA5 gene has devastating impacts, with affected individuals reaching few developmental milestones and experiencing frequent and early-onset seizures. With CURE Epilepsy funding, scientists created a first-of-its-kind organoid model for the disorder. This unique cell-based system allows researchers to study how a gene mutation causes developmental defects and identify potential ways to treat them.
The UBA5 mutation is recessive, meaning two copies of the mutated gene are needed to trigger encephalopathy. However, one of the copies is usually hypomorphic, meaning one of the genes is still partially functioning.
“If you look at genetic databases, some people have two copies of that hypomorphic allele and are perfectly healthy,” said Heather Mefford, MD, PhD, St. Jude Pediatric Translational Neuroscience Initiative and Department of Cell & Molecular Biology. “This told us that if we could coax the cells to make enough of the copy that doesn’t work as well, it might be a potential therapy.”
Mefford’s team used what are called induced pluripotent stem cells from patients with UBA5-associated encephalopathy to grow organoids. With this model, the researchers explored the genetic architecture of the disease, comparing it to healthy control organoids. The UBA5 organoids were strikingly different from the controls in how they functioned. The organoid models also revealed defects in the development of certain cell types.
Based on these findings, the researchers explored interventions to reverse the effects of UBA5 mutation. They found that boosting the expression of the existing partially functioning copy of UBA5 reversed the mutation’s effects, demonstrating a potential treatment route that merits further investigation.