Discoveries made by Dr. Mingshan Xue, Caroline DeLuca endowed scholar and principal investigator at Texas Youngsters’s Duncan Neurological Analysis Institute (Duncan NRI), Cain Foundation Laboratories, and affiliate professor at Baylor School of Medication, have superior our understanding of a devastating childhood epilepsy situation attributable to adjustments within the STXBP1 gene. Dr. Xue developed a proprietary mouse mannequin that replicates this situation, referred to as STXBP1-related dysfunction, and demonstrated proof-of-concept {that a} particular strategy to therapy – referred to as adeno-associated virus (AAV) gene remedy – may reverse the illness.
Now, Texas Youngsters’s Hospital will take part in Capsida Biotherapeutics’ multicenter SYNRGY scientific trial for an investigational new gene remedy, CAP-002, which was developed by Capsida for the situation in collaboration with Dr. Xue. Dr. Hsiao-Tuan Chao, principal investigator on the Duncan NRI, Cain Basis Laboratories, and McNair scholar and assistant professor at Baylor, will assist lead the SYNRGY Part 1/2a trial at Texas Youngsters’s.
“We’ve discovered a possible new remedy – we predict, we hope,” stated Elizabeth, whose daughter, Caroline, was recognized with STXBP1-related dysfunction at Texas Youngsters’s when she was 12 years outdated – one of many first youngsters on the earth recognized. “I believe it’s going to be life-changing for the youngsters and their households.”
Capsida, the corporate growing the gene remedy, introduced the U.S. Meals and Drug Administration (FDA) clearance of their Investigational New Drug (IND) utility in Could 2025.
STXBP1-related dysfunction, or STXBP1-developmental epileptic encephalopathy (STXBP1-DEE), is a uncommon neurodevelopmental situation and one of the crucial frequent genetic causes of childhood epilepsy, stemming from a change within the STXBP1 gene. It causes devastating seizures, motor difficulties, and cognitive impairments and impacts as much as one in 26,000 youngsters – together with Caroline, somewhat woman who liked to swim, sing “Completely happy Birthday,” and watch Broadway exhibits like Mamma Mia.
In 2009, when she was 12 years outdated, after a number of critical brushes with sickness and extreme episodes of epilepsy, Caroline was recognized with STXBP1-related dysfunction.
“We noticed her, from someday to the following, lose the power to stroll,” stated Caroline’s mom, Elizabeth. “Six weeks later, we came upon that she had one thing referred to as STXBP1 – properly, I don’t even know if that they had a reputation for it on the time, she was the primary youngster on the earth recognized.”
At that time, it was an unsolved situation, with no treatment out there wherever.
Hear Elizabeth’s story in this special video.
A mom’s story
Elizabeth fought for her daughter’s life. She took her to see three neurologists in every week, stayed up all night time researching the genetic change, snuggled up beside her to observe her as she slept, and began a college for particular youngsters like Caroline.
Elizabeth together with her daughter, Caroline, one of many first youngsters recognized with STXBP1-related dysfunction.
Quickly, Elizabeth’s seek for solutions led her to world-renowned neurogeneticist Dr. Huda Zoghbi, who was acclaimed for fixing the “unsolvable” and was working with a bunch of daring philanthropists to deliver a brand new imaginative and prescient to life: a one-of-a-kind institute devoted to understanding and growing remedies for debilitating mind illnesses. A number of years after this institute was based and have become the Duncan NRI, Dr. Zoghbi introduced an excellent younger investigator – Dr. Mingshan Xue – to fulfill Caroline and her household.
“I keep in mind he got here to the home,” stated Elizabeth. “Caroline and I have been there, and in the midst of the assembly, Caroline went into an enormous seizure. Mingshan had seen this dysfunction earlier than in fruit flies and zebra fish, nevertheless it wasn’t the identical as somewhat woman. She completed, and we went again into the assembly, however I may inform one thing had modified for him. When he hugged us goodbye, he instructed us, ‘I’ll be again,’ and I knew proper then he was coming to Houston.”
“I’m a neuroscientist by coaching, and I’d simply completed my post-doctorate in San Diego,” stated Dr. Xue. “I used to be deciding the place to go subsequent to open my first analysis lab. I had by no means studied a neurodevelopmental dysfunction or an epilepsy situation earlier than. However once I met Caroline, I knew I wanted to assist her. Caroline modified all the pieces for me.”
A seek for solutions
After assembly Caroline, Dr. Xue joined the Duncan NRI in 2014 and – with beneficiant help from Elizabeth and her household – started constructing a analysis program devoted to fixing STXBP1-related dysfunction, with the last word objective to develop a remedy that tackles the foundation causes of the illness – serving to Caroline and all youngsters like her.
Within the first stage of his work, Dr. Xue developed a proprietary mouse mannequin that replicates STXBP1-related dysfunction and demonstrated proof-of-concept {that a} gene remedy strategy – utilizing a viral vector referred to as “adeno-associated virus” (AAV) that carries the wholesome STXBP1 gene into the mind – may reverse the dysfunction. All through his work, Elizabeth would go to Dr. Xue in his lab and take Caroline together with her to see the mice.
“Caroline has at all times been my inspiration,” stated Dr. Xue. “Elizabeth was our greatest cheerleader and collaborator, urging us to strive various things, and even telling us sure signs Caroline had that we didn’t find out about. With out Caroline, Elizabeth, and their household, none of our work would have been potential.”
“There was a sense of openness and collaboration from Dr. Xue, Dr. Zoghbi and the Duncan NRI that I’ve by no means discovered wherever else,” stated Elizabeth. “I stroll into that constructing and I can simply really feel the hope.”
To realize the extent of widespread protein restoration wanted in people, Dr. Xue entered right 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 research, may obtain widespread expression of STXBP1 protein within the mind. Capsida’s engineered capsid is considerably detargeted from off-target organs, such because the liver, following intravenous administration in preclinical research.
Within the first half of 2024, the laboratory of Dr. Xue, in collaboration with Capsida, had a serious breakthrough. In revolutionary preclinical research, they recognized the minimal quantity of STXBP1 genetic materials wanted to alleviate signs in animal fashions of STXBP1-related dysfunction, with long-lasting results. Additionally they recognized doses that achieved greater ranges of STXBP1 and better symptom correction. The discoveries marked an thrilling turning level within the seek for a brand new efficient remedy and have now led to the scientific trials set to start out in 2025.
“This investigational new gene remedy is a very excellent achievement and is a ravishing instance of our mission on the Duncan NRI,” stated Dr. Huda Zoghbi, founding director of Texas Youngsters’s Duncan NRI, distinguished service professor at Baylor, and investigator on the Howard Hughes Medical Institute. “Dr. Xue’s discoveries have charted new paths ahead for therapeutic growth for STXBP1-related dysfunction, and within the coming years we hope this can assist change outcomes for the youngsters and adults affected by this dysfunction. Caroline impressed Dr. Xue and others on the Duncan NRI to push as onerous as we are able to to develop remedies for devastating neurological problems.”
Dr. Chao with a Texas Youngsters’s affected person, who suffers from STXBP1-related dysfunction.
Hope for the long run: “We can assist the infants”
At 18 years outdated, Caroline misplaced her brave battle with STXBP1-related dysfunction. Into her ultimate years, she continued to work together with her mom and Dr. Xue of their race to discover a new remedy.
“Caroline was at all times keen to assist,” stated Elizabeth. “She would fortunately give us her arm for an IV to present blood. I’d inform her, ‘that is to assist the infants,’ and he or she would stick out her arm straight away. She knew she was serving to the hundreds of kids who would come after her. As she at all times stated, now, ‘we can assist the infants.’”
“I maintain a photograph of Caroline on my desk,” stated Dr. Xue. “When one thing is difficult, or we’ve run into an issue within the analysis, I take a look at her picture and I really feel like she’s telling me, ‘Nothing can’t be overcome.’”
Of their years of analysis and collaboration with Dr. Xue, Elizabeth and Caroline created a neighborhood of households and youngsters with STXBP1-related dysfunction. Lots of them go to Elizabeth and her household in Houston and plan to stick with her in the course of the scientific trial.
“That’s what I’m wanting ahead to, is to see it go from an thought to a mouse mannequin to a scientific trial for people, to, we hope, assist the infants,” stated Elizabeth.
In loving reminiscence of Caroline.
With questions relating to the upcoming multicenter SYNRGY scientific trial at Texas Youngsters’s Hospital, please attain out to Dr. Hsiao-Tuan Chao and her analysis staff at chao-lab@bcm.edu.
