St. Jude expands work in catastrophic diseases to pediatric epilepsy

When St. Jude Children’s Research Hospital was founded 63 years ago, it was fueled by a profound promise that no child should die in the dawn of life. Not from cancer, nor other catastrophic diseases, including blood disorders and infectious diseases. 

Today, that work includes pediatric neurological disorders. The work is part of a six-year, $12.9 billion strategic plan to improve cure rates for pediatric cancer and life-threatening diseases worldwide. 

Despite the high prevalence of pediatric neurological diseases, opportunities for developing therapies for them have been limited by poor understanding of the cause of most of these diseases. 

Heather Mefford, MD, PhD, is part of the team of doctors and researchers hoping to change that through her work at St. Jude.  

Mefford joined the Center for Pediatric Neurological Disease Research at St. Jude in 2021 to serve as an attending physician and continue her renowned research program determining the genes responsible for rare forms of epilepsy and neurodevelopmental disorders.  

In this interview, Mefford explains the work St. Jude is doing to better understand and treat pediatric neurological disorders. 

Q: What brought you to St. Jude?

A: I came to St. Jude to be part of the Pediatric Translational Neuroscience Initiative, which represents a commitment of St. Jude to do what they did for pediatric cancers, but to do it now for rare pediatric neurological diseases. My research is dedicated to understanding severe pediatric epilepsy or seizure conditions and related developmental disorders. I was excited to hear that St. Jude was investing in neurologic disease research.  

St. Jude has a long, rich history of implementing clinical trials, developing new treatments and doing good basic discovery science. Most of this has been dedicated to disorders like cancer, immunologic disease and infectious disease. So, when they started to talk about doing this for a pediatric neurologic disease, I knew this was the right time for me to think about making a move.

I wanted to see my career move from understanding genetic causes of disease to translating that into models of disease where we can better understand the disease, to testing new therapies. We want to move some of those therapies into the clinic. St. Jude has the history, the resources and the expertise to be able to make this a reality. 

Q: What is pediatric epilepsy? 

A: Pediatric epilepsy is defined by having multiple seizures, and seizures that can come in many forms, with onset sometime in childhood. At St. Jude, we study the most severe end of the spectrum, and these are disorders where the seizures begin in the first weeks to months after birth. They're also associated with significant developmental impact, meaning that many of these patients don't meet their developmental milestones and have long-term poor outcomes.  

We study the most severe end of the spectrum (for pediatric epilepsy) because there is the greatest need for developing novel therapies that can treat and perhaps someday cure the disease. 

Q: Can you provide an overview of pediatric epilepsy research at St. Jude? How did it start and where is it now?

A: As a physician scientist, I'm able to see patients in the clinic who have epilepsy conditions and try to diagnose them from a genetic standpoint. If they already have a diagnosis, we try to educate them about that diagnosis. We also have the opportunity to enroll those patients in our research program.

The research program is dedicated to three facets: first, understand and identify new genetic causes for epilepsy; second, take specific genetic epilepsy conditions using patient cells and develop models of disease so that we can study those cells in the laboratory. 

The third aim is to use those models to test potential novel therapies that are targeted for the specific genetic cause. 

This is important because many of the patients with severe early onset epilepsies don't have good therapies. Their seizures continue despite using multiple available anti-seizure medications. And the medications that are used for seizures don't really help the developmental aspect of the disease.  

We are working to identify and then target the root genetic cause of disease to have an impact. 

Q: How does St. Jude foster collaboration both in-house, as well as with other institutions, and why is that collaboration important? 

A: St. Jude is a very collaborative research and clinical care environment. At St. Jude, we are lucky to have collaborators who are able to evaluate our patients clinically alongside those of us in the lab. We can learn from them how to evaluate disease, how to develop a treatment for our patients and measure what the impact of that treatment is.  

We have a lot of outside collaborations for our epilepsy research, including international collaborations. They help us identify patients who need a genetic diagnosis or need a new therapy or want to connect with a patient advocacy group. We have patients and collaborators as far as Australia and South Africa.  

We travel to meetings in Europe to help get the word out and to foster new collaborations to facilitate our research. The diseases that we study are extremely rare, so it's important to have collaborations because we can't do this as a single laboratory or even as a single institution. Engaging researchers from around the world who see patients and study epilepsy or similar diseases is really important to move the entire field forward together. 

Q: Can you describe the progress in your research thus far and what the future of this work looks like?

A: We've made a lot of progress in understanding the genes, the genetic changes responsible for severe pediatric epilepsy. What that means today is clinically we are able to provide a genetic diagnosis for nearly 50 percent of patients.

That’s a huge impact over the past decade or so of research. And as a scientist, it has been exciting to discover those genes and genetic causes. As a physician, the frustration is that we can provide a genetic diagnosis, but we often can't provide a specific treatment.  

The current goal of our research is really to understand what goes wrong when you have a genetic change that causes epilepsy. Then, we aim to model the diseases using cells from patients or cells that we engineer using the resources here at St. Jude, and next we test new therapies that go right at that genetic change or the gene or the pathway that's changed so that we can have an impact on the root cause of disease and perhaps modify the disease — or even in the future, someday prevent the disease. 

Q: How do St. Jude supporters make the work you just outlined possible?  

A: Because of the support we receive, when I got to St. Jude, I was quickly able to build a team of talented scientists within the first year that enabled us to really have a solid foundation for doing the studies that we wanted to do.

In addition, because of the funding and the facilities here at St. Jude, my lab was connected right away with the genome engineering core and the sequencing core. We were able to work with them collaboratively on what types of projects we wanted to do to advance our work.  

Part of my decision to move to St. Jude was the support offered to faculty members, investigators, researchers and clinicians here at St. Jude to sustain the research that we do.