Tufts Researcher Takes on Epilepsy After Daughter’s Diagnosis
In 2021, Madeleine Oudin, associate professor of biomedical engineering at the School of Engineering, noticed that her three-month-old daughter’s eyes were moving strangely. She took a video and sent it to her pediatrician, who told her to take Margot to the emergency department at Boston Children’s Hospital.
The eye movements, it turned out, were the result of seizures and Margot was diagnosed with epilepsy.
Less than three years later, Oudin has added a focus on epilepsy to her research lab, where she was already studying cancer.
“I felt like if I couldn’t really do anything to stop my daughter from seizing or help her develop, I could try to do something in the lab to contribute to the field,” she said.
Finding Genetic Mutations
Seizures in infants can be caused by many factors, including temporary conditions like fever. In Margot’s case, genetic testing showed that her seizures were caused by mutations in a part of a gene called SCN8A that contains instructions for building ion channels, which are portals in cell membranes. Ion channels have many functions in the body; in the brain, they help transmit electrical signals.
Margot’s case of SCN8A epilepsy is severe: she’s unable to see, hold her head up, or eat using her mouth. In her three years of life, she’s had more than 20,000 seizures, has been in the hospital 17 times, and has tried 11 anti-seizure medications.
Despite Margot’s challenges, Oudin said, “She’s a happy girl. She loves to swim and go outside and listen to music. We’ve learned to take advantage of life in a different way with her.”
A Scientific Pivot
Even though Oudin was making waves with her research on cancer metastasis (and continues to do so), she was well positioned to take on epilepsy. She had a Ph.D. in neuroscience and was surrounded by colleagues with relevant expertise, including Chris Dulla, professor and interim chair of the neuroscience department at Tufts University School of Medicine, and her husband, Christopher Burge, professor of biology at the Massachusetts Institute of Technology.
On top of all that, Oudin’s cancer research related to ion channels, the same cellular structures that are affected by Margot’s mutations.
“It’s weird,” she said, “I do feel like all my training up to now has prepared me for this: to be Margot’s mom and take this on, to help her and her community. I do feel like this happened for a reason.”
Gathering Expertise and Resources
Soon after Margot’s diagnosis, Oudin reached out to Dulla, who has a long history of epilepsy research. “I could never have done this without Chris,” Oudin said.
Dulla brought Oudin up to speed on epilepsy research and connected her with other experts. And Oudin taught Dulla everything she knew about ion channels, which hadn’t been part of his research before. “Madeleine is a dynamo,” Dulla said. “She has so much energy to push the understanding of this ion channel that we’re working on.”
They have already raised $50,000 on Oudin’s lab website, won a small seed grant from the American Epilepsy Society and were recently awarded a $700,000 grant from the Mathers Foundation.
Both of them marvel at the speed with which this productive partnership is lifting off. “The set of coincidences of a group of people who each have the right expertise to move this forward very quickly is amazing,” Dulla said.
Investigating a New Therapeutic Option
During childhood, SCN8A makes a different version of the ion channel protein than in adulthood. Margot’s mutations affect the childhood version.
Would it be possible to stop Margot’s seizures by persuading SCN8A to switch over to making the adult version? And if the seizures stopped, would she be able to achieve some of the developmental milestones she’s missed? These are the questions Oudin and her colleagues are aiming to answer.
The childhood and adult versions are created using the same genetic material in different combinations, as you might use the same building blocks to assemble two different structures. This is called alternative splicing and it’s a basic function that occurs naturally in many genes.
Chris Burge, Oudin’s husband, has studied alternative splicing for 20 years; he was the one who figured out that Margot’s mutations were in the region of SCN8A that switches from a childhood version to an adult one.
That realization pointed to a new treatment shown to change alternative splicing. Molecules called antisense oligonucleotides, or ASOs, can be engineered to bind to certain parts of genetic material to influence alternative splicing.
“We think the therapeutic option for this is to use an ASO to switch the splicing to include the correct adult version and prevent the mutated childhood version from being a part of the protein,” Oudin said.
Rare Solution, Big Impact
Oudin and Burge applied to n-Lorem, a nonprofit foundation that develops ASOs for patients with rare mutations, and Margot was accepted. “We hope within a couple of years Margot will be injected with a treatment,” Oudin said.
Margot is the only known person with her exact mutations. However, many children with epilepsy have mutations in other parts of SCN8A or mutations in other genes related to other ion channels. So, if the ASO treatment works for Margot, the technique could help other children as well.
“Most drug discovery for epilepsy is made possible thanks to rare disease,” Dulla said. “If we find something that works for SCN8A, it could be applied to lots of other sodium channel mutations that would benefit from the splice-switching approach.”
Meanwhile, Oudin and Dulla are hard at work to advance the science related to SCN8A, ion channels, and epilepsy.
Haley Dame, a graduate student in the Genetics, Molecular, and Cellular Biology program at the Graduate School for Biomedical Sciences, is working on the epilepsy project for her doctoral thesis, advised by Oudin, Dulla, and Burge. The goals of the project are to illuminate more about how, why, and when SCN8A’s alternative splicing occurs in healthy development and to investigate the impact of switching from the childhood version to the adult version earlier in life than usual in both healthy mice and those with Margot’s mutations.
“No one is really studying this region of SCN8A and the alternative splicing,” Oudin said, “so we felt like we could bring in a lot of new and exciting science.”
Motivation from Margot
There are thousands of scientific steps between here and the answer to the ultimate question, which is, in Oudin’s words, “Can we correct and treat this disorder?”
But none of the team members are daunted. They are fueled by a happy little girl who loves life, Margot.
“Margot is amazing,” Dulla said. “It’s such a wonderful experience for me to get to take my scientific training and use it in such an immediately useful way.”
Dame agreed: “I don’t think a lot of researchers get to see what they are working for,” she said. “It’s really rewarding.”
As for Oudin, her daughter has motivated her not only to become an epilepsy researcher, but also to become a patient advocate and an active member of the SCN8A community.
“Having the perspective of being both a scientist and a caregiver and patient advocate is really unique,” she said. “You just don’t know until you live through it. I can understand the needs of patients and the community as well as the research and biology behind it.”
Oudin now serves on the board of the International SCN8A Alliance, where she shares both her scientific expertise and her personal experience.
“It’s been a crazy couple of years, but I’m excited that I can contribute in a meaningful way,” Oudin said, “and I could not have done it without the community at Tufts.”