A mother’s mission to help her daughter leads to a clinical trial

Discoveries made by Dr. Mingshan Xue, Caroline DeLuca endowed scholar and principal investigator at Texas Children’s Duncan Neurological Research Institute (Duncan NRI), Cain Foundation Laboratories, and associate professor at Baylor College of Medicine, have advanced our understanding of a devastating childhood epilepsy condition caused by changes in the STXBP1 gene. Dr. Xue developed a proprietary mouse model that replicates this condition, called STXBP1-related disorder, and demonstrated proof-of-concept that a specific approach to treatment – called adeno-associated virus (AAV) gene therapy – could reverse the disease. 

Now, Texas Children’s Hospital will participate in Capsida Biotherapeutics’ multicenter SYNRGY clinical trial for an investigational new gene therapy, CAP-002, which was developed by Capsida for the condition in collaboration with Dr. Xue. Dr. Hsiao-Tuan Chao, principal investigator at the Duncan NRI, Cain Foundation Laboratories, and McNair scholar and assistant professor at Baylor, will help lead the SYNRGY Phase 1/2a trial at Texas Children’s.

“We’ve found a potential new therapy – we think, we hope,” said Elizabeth, whose daughter, Caroline, was diagnosed with STXBP1-related disorder at Texas Children’s when she was 12 years old – one of the first children in the world identified. “I think it’s going to be life-changing for the children and their families.”

Capsida, the company developing the gene therapy, announced the U.S. Food and Drug Administration (FDA) clearance of their Investigational New Drug (IND) application in May 2025. 

STXBP1-related disorder, or STXBP1-developmental epileptic encephalopathy (STXBP1-DEE), is a rare neurodevelopmental condition and one of the most common genetic causes of childhood epilepsy, stemming from a change in the STXBP1 gene. It causes devastating seizures, motor difficulties, and cognitive impairments and affects up to one in 26,000 children – including Caroline, a little girl who loved to swim, sing “Happy Birthday,” and watch Broadway shows like Mamma Mia.

In 2009, when she was 12 years old, after several serious brushes with illness and severe episodes of epilepsy, Caroline was diagnosed with STXBP1-related disorder.

“We saw her, from one day to the next, lose the ability to walk,” said Caroline's mother, Elizabeth. “Six weeks later, we found out that she had something called STXBP1 – well, I don’t even know if they had a name for it at the time, she was the first child in the world identified.”

At that point, it was an unsolved condition, with no cure available anywhere.

Hear Elizabeth's story in this special video.

A mother’s story

Elizabeth fought for her daughter’s life. She took her to see three neurologists in a week, stayed up all night researching the genetic change, snuggled up beside her to watch her as she slept, and started a school for special children like Caroline.

Elizabeth with her daughter, Caroline, one of the first children diagnosed with STXBP1-related disorder.

Soon, Elizabeth’s search for answers led her to world-renowned neurogeneticist Dr. Huda Zoghbi, who was acclaimed for solving the “unsolvable” and was working with a group of bold philanthropists to bring a new vision to life: a one-of-a-kind institute dedicated to understanding and developing treatments for debilitating brain diseases. A few years after this institute was founded and became the Duncan NRI, Dr. Zoghbi brought a brilliant young investigator – Dr. Mingshan Xue – to meet Caroline and her family. 

“I remember he came to the house,” said Elizabeth. “Caroline and I were there, and in the middle of the meeting, Caroline went into a big seizure. Mingshan had seen this disorder before in fruit flies and zebra fish, but it wasn’t the same as a little girl. She finished, and we went back into the meeting, but I could tell something had changed for him. When he hugged us goodbye, he told us, ‘I’ll be back,’ and I knew right then he was coming to Houston.”

“I’m a neuroscientist by training, and I’d just finished my post-doctorate in San Diego,” said Dr. Xue. “I was deciding where to go next to open my first research lab. I had never studied a neurodevelopmental disorder or an epilepsy condition before. But when I met Caroline, I knew I needed to help her. Caroline changed everything for me.”

A search for answers

After meeting Caroline, Dr. Xue joined the Duncan NRI in 2014 and – with generous support from Elizabeth and her family – began building a research program dedicated to solving STXBP1-related disorder, with the ultimate goal to develop a therapy that tackles the root causes of the disease – helping Caroline and all children like her. 

In the first stage of his work, Dr. Xue developed a proprietary mouse model that replicates STXBP1-related disorder and demonstrated proof-of-concept that a gene therapy approach – using a viral vector called “adeno-associated virus” (AAV) that carries the healthy STXBP1 gene into the brain – could reverse the disorder. Throughout his work, Elizabeth would visit Dr. Xue in his lab and take Caroline with her to see the mice.

“Caroline has always been my inspiration,” said Dr. Xue. “Elizabeth was our biggest cheerleader and collaborator, urging us to try different things, and even telling us certain symptoms Caroline had that we didn’t know about. Without Caroline, Elizabeth, and their family, none of our work would have been possible.” 

“There was a feeling of openness and collaboration from Dr. Xue, Dr. Zoghbi and the Duncan NRI that I’ve never found anywhere else,” said Elizabeth. “I walk into that building and I can just feel the hope.”

To achieve the level of widespread protein restoration needed in humans, Dr. Xue entered into a collaboration with Capsida Biotherapeutics. Capsida’s proprietary engineering platform enabled identification of an engineered capsid that, when paired with STXBP1 therapeutic cargo in preclinical studies, could achieve widespread expression of STXBP1 protein in the brain. Capsida’s engineered capsid is significantly detargeted from off-target organs, such as the liver, following intravenous administration in preclinical studies.

In the first half of 2024, the laboratory of Dr. Xue, in collaboration with Capsida, had a major breakthrough. In innovative preclinical studies, they identified the minimal amount of STXBP1 genetic material needed to alleviate symptoms in animal models of STXBP1-related disorder, with long-lasting effects. They also identified doses that achieved higher levels of STXBP1 and greater symptom correction. The discoveries marked an exciting turning point in the search for a new effective therapy and have now led to the clinical trials set to start in 2025.

“This investigational new gene therapy is a truly outstanding achievement and is a beautiful example of our mission at the Duncan NRI,” said Dr. Huda Zoghbi, founding director of Texas Children’s Duncan NRI, distinguished service professor at Baylor, and investigator at the Howard Hughes Medical Institute. “Dr. Xue’s discoveries have charted new paths forward for therapeutic development for STXBP1-related disorder, and in the coming years we hope this will help change outcomes for the children and adults affected by this disorder. Caroline inspired Dr. Xue and others at the Duncan NRI to push as hard as we can to develop treatments for devastating neurological disorders.”   

Dr. Chao with a Texas Children’s patient, who suffers from STXBP1-related disorder. 

Hope for the future: “We can help the babies”

At 18 years old, Caroline lost her courageous fight with STXBP1-related disorder. Into her final years, she continued to work with her mother and Dr. Xue in their race to find a new therapy. 

“Caroline was always willing to help,” said Elizabeth. “She would happily give us her arm for an IV to give blood. I would tell her, ‘this is to help the babies,’ and she would stick out her arm right away. She knew she was helping the thousands of children who would come after her. As she always said, now, ‘we can help the babies.’”

“I keep a photo of Caroline on my desk,” said Dr. Xue. “When something is challenging, or we’ve run into a problem in the research, I look at her photo and I feel like she’s telling me, ‘Nothing cannot be overcome.’” 

In their years of research and collaboration with Dr. Xue, Elizabeth and Caroline created a community of families and children with STXBP1-related disorder. Many of them visit Elizabeth and her family in Houston and plan to stay with her during the clinical trial.

“That’s what I’m looking forward to, is to see it go from an idea to a mouse model to a clinical trial for humans, to, we hope, help the babies,” said Elizabeth. 

In loving memory of Caroline.

With questions regarding the upcoming multicenter SYNRGY clinical trial at Texas Children’s Hospital, please reach out to Dr. Hsiao-Tuan Chao and her research team at chao-lab@bcm.edu.