UBA5 disorder is considered an ultra-rare condition which affects brain function, but a new cortical organoid model presented in Science Translational Medicine today reveals key defects which may be targetable. Pictured is first author Helen Chen, PhD, formerly of the Pediatric Translational Neuroscience Initiative and Department of Cell & Molecular Biology, corresponding author Heather Mefford, MD, PhD, and Emily Bonkowski, Pediatric Translational Neuroscience Initiative and Department of Cell & Molecular Biology, and Aidan Blan, formerly of the Pediatric Translational Neuroscience Initiative and Department of Cell & Molecular Biology.
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. Scientists at St. Jude Children’s Research Hospital created a first-of-its-kind cortical organoid model for the disorder, studying how it causes developmental defects and identifying potential ways to treat it. The findings were published today in Science Translational Medicine.
Treatment for UBA5-associated encephalopathy is currently limited to addressing the symptoms and managing the severe deficiencies in muscle tone and physical ability caused by the disorder. The mutation is recessive, meaning two copies of the mutated gene are needed to trigger the 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.”
“Neurodevelopmental disorders are challenging to study in model organisms. Moreover, the genetic landscape for UBA5-associated encephalopathy is an important factor,” said first author Helen Chen, PhD, formerly of the St. Jude Pediatric Translational Neuroscience Initiative and Department of Cell & Molecular Biology. “It was imperative for us to use patient-derived models, such as organoids, to model the disorder and test proposed therapies.”
Mefford and her team leveraged technological advances to create a model that would help them understand how UBA5-associated encephalopathy causes its symptoms, providing insight into how physicians could treat the disorder more effectively.
Stunted GABAergic interneuron growth unbalances signaling
Mefford’s team used induced pluripotent stem cells from patients with UBA5-associated encephalopathy to grow cortical organoids. These three-dimensional cell cultures mimic the organization and development of regions of the brain. With this model, the researchers explored the genetic architecture of the disease, comparing it to healthy control models.
The organoids were strikingly different from the controls in how they functioned. “The patient organoids are smaller, grow slower and have increased but less organized electrical activity,” Mefford said. “This is a key point because most of these patients have seizures that are hard to treat.”
The cortical organoid models also revealed developmental defects, including stunted GABAergic interneuron growth. “Seizures occur due to an imbalance in neuronal excitation and inhibition. GABAergic cells are inhibitory, meaning they prevent hyperactivity, which may explain why these patients have seizures,” Mefford said. “It also tells us something specific is going wrong in development related to these cells compared to others.”
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.
“We are excited about the initial findings from our research, and we will continue to use our patient-derived model to pinpoint the therapeutic window for treatment while focusing on establishing the minimum response dose and potential delivery approaches,” said Chen.
Rare diseases, including UBA5-associated encephalopathy, are embodied by tight-knit and active advocacy groups. “The families and advocacy groups were and are critical to the research and remain very engaged. They’re hopeful but also understanding that the research that’s done will impact future affected individuals,” Mefford expressed. “Having them involved is really impactful.”
Authors and funding
The study’s other authors are Christy LaFlamme, Yong-Dong Wang, Aidan Blan, Nikki Koehler, Renata Mendonca Moraes, Athena Olszewski, Edith Almanza Fuerte, Emily Bonkowski, Richa Bajpai, Alfonso Lavado and Shondra M. Pruett-Miller, all of St. Jude.
The study was supported by a Pediatric 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.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.