In a groundbreaking collaborative study, researchers from Children’s Hospital of Philadelphia (CHOP) and Washington University School of Medicine found preclinical evidence for a new type of gene therapy that could prevent enteric neuron degeneration, gradual loss of nerve cells in the digestive system, in the fatal disorder Batten disease as well as other neurodegenerative disorders. The findings were recently published in the journal Science Translational Medicine.
Batten disease refers to a group of inherited nervous system disorders in which a child lacks a crucial enzyme that breaks down and recycles cellular waste. Also known as neuronal ceroid lipofuscinosis, the disease is named after the accumulated material inside the cells. Not having these enzymes causes progressive brain damage that leads to death.
The exact number of children with Batten disease remains unknown; however, some researchers have estimated it affects around three out of every 100,000 children in the U.S.
Jonathan D. Cooper, PhD, Professor of Pediatrics, Genetics and Neurology at Washington University School of Medicine, wanted to investigate why debilitating digestive issues were affecting Batten disease patients, since that disease is associated with the brain. This led to the study of the enteric nervous system that lines the bowel wall and the effect of Batten disease on bowel nervous system function. His new work shows enteric neurons in two Batten disease models degenerate in the bowel, parallelling neurodegeneration long known to occur in brain and spinal cord.
Doctors had informed the parents that their children with Batten disease could succumb to blindness, seizures, dementia and an inability to walk, and would die in childhood. However, parents told Cooper they felt unprepared for the severe constipation and intestinal issues their children faced.
Cooper reached out to Robert O. Heuckeroth, MD, PhD, a pediatric gastroenterologist at CHOP and a professor of pediatrics and of cell and developmental biology at the University of Pennsylvania Perelman School of Medicine.
Together, the scientists discovered that while Batten disease ravages nerve cells in the brain and spinal cord, it also kills neurons that are part of the GI tract’s enteric nervous system. Their research on Batten disease in preclinical models and in colons from children who died of Batten disease showed that nerve cell degeneration in the bowel occurs in parallel with events in the brain, following a similar pattern and timeline.
The basis for treating these diseases is to supply a working copy of the defective gene. This is supplied by a gene therapy virus that instructs cells to make this missing enzyme. In a preclinical model of Batten disease, the gene therapy prevented the loss of many nerve cells in the bowel and prevented related problems with bowel function.
The researchers have begun to apply their findings to other forms of Batten disease and similar neurodegenerative conditions in children such as the mucopolysaccharidoses, another group of rare inherited diseases caused by enzyme deficiencies that thwart a cell’s ability to break down material.
“The enteric nervous system controls most aspects of bowel function, including motility, epithelial biology, blood flow and immune cell function,” said Heuckeroth. "For this reason, degeneration of bowel neurons causes vomiting, distension, constipation, abdominal pain, malnutrition and a predisposition to bowel inflammation, sepsis and death. This work shows that a serious disease of the enteric nervous system could be treated by gene therapy.”
Cooper and Heuckeroth noted that future studies will focus on providing simultaneous gene therapy to both the brain and bowel, which they think is necessary for optimal outcomes.
“We believe our preclinical studies demonstrate a novel and highly promising way to successfully treat GI conditions with gene therapy,” said Cooper, the study’s co-senior author. “Importantly, we also established that the GI issues were not secondary to the neurological changes in the brain or spinal cord caused by the disease, but happen in the bowel itself.”
This research was supported by The National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) grants R21 NS116574, R01 NS100779, R01DK129691; Noah’s Hope/Hope 4 Bridget; The Lehrman Family Fund; the Department of Pediatrics at WashU Medicine; Irma and Norman Braman Endowment; Suzi and Scott Lustgarten Center Endowment; and the Children’s Hospital of Philadelphia Fronter Program Center for Precision Diagnosis and Therapy for Pediatric Motility Disorders.
Ziółkowska et al. Gene therapy prevents bowel dysmotility, enteric neuron degeneration and extends survival in lysosomal storage disorders. Science Translational Medicine. Jan. 15, 2025. DOI: 10.1126/scitranslmed.adj1445
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In a groundbreaking collaborative study, researchers from Children’s Hospital of Philadelphia (CHOP) and Washington University School of Medicine found preclinical evidence for a new type of gene therapy that could prevent enteric neuron degeneration, gradual loss of nerve cells in the digestive system, in the fatal disorder Batten disease as well as other neurodegenerative disorders. The findings were recently published in the journal Science Translational Medicine.
Batten disease refers to a group of inherited nervous system disorders in which a child lacks a crucial enzyme that breaks down and recycles cellular waste. Also known as neuronal ceroid lipofuscinosis, the disease is named after the accumulated material inside the cells. Not having these enzymes causes progressive brain damage that leads to death.
The exact number of children with Batten disease remains unknown; however, some researchers have estimated it affects around three out of every 100,000 children in the U.S.
Jonathan D. Cooper, PhD, Professor of Pediatrics, Genetics and Neurology at Washington University School of Medicine, wanted to investigate why debilitating digestive issues were affecting Batten disease patients, since that disease is associated with the brain. This led to the study of the enteric nervous system that lines the bowel wall and the effect of Batten disease on bowel nervous system function. His new work shows enteric neurons in two Batten disease models degenerate in the bowel, parallelling neurodegeneration long known to occur in brain and spinal cord.
Doctors had informed the parents that their children with Batten disease could succumb to blindness, seizures, dementia and an inability to walk, and would die in childhood. However, parents told Cooper they felt unprepared for the severe constipation and intestinal issues their children faced.
Cooper reached out to Robert O. Heuckeroth, MD, PhD, a pediatric gastroenterologist at CHOP and a professor of pediatrics and of cell and developmental biology at the University of Pennsylvania Perelman School of Medicine.
Together, the scientists discovered that while Batten disease ravages nerve cells in the brain and spinal cord, it also kills neurons that are part of the GI tract’s enteric nervous system. Their research on Batten disease in preclinical models and in colons from children who died of Batten disease showed that nerve cell degeneration in the bowel occurs in parallel with events in the brain, following a similar pattern and timeline.
The basis for treating these diseases is to supply a working copy of the defective gene. This is supplied by a gene therapy virus that instructs cells to make this missing enzyme. In a preclinical model of Batten disease, the gene therapy prevented the loss of many nerve cells in the bowel and prevented related problems with bowel function.
The researchers have begun to apply their findings to other forms of Batten disease and similar neurodegenerative conditions in children such as the mucopolysaccharidoses, another group of rare inherited diseases caused by enzyme deficiencies that thwart a cell’s ability to break down material.
“The enteric nervous system controls most aspects of bowel function, including motility, epithelial biology, blood flow and immune cell function,” said Heuckeroth. "For this reason, degeneration of bowel neurons causes vomiting, distension, constipation, abdominal pain, malnutrition and a predisposition to bowel inflammation, sepsis and death. This work shows that a serious disease of the enteric nervous system could be treated by gene therapy.”
Cooper and Heuckeroth noted that future studies will focus on providing simultaneous gene therapy to both the brain and bowel, which they think is necessary for optimal outcomes.
“We believe our preclinical studies demonstrate a novel and highly promising way to successfully treat GI conditions with gene therapy,” said Cooper, the study’s co-senior author. “Importantly, we also established that the GI issues were not secondary to the neurological changes in the brain or spinal cord caused by the disease, but happen in the bowel itself.”
This research was supported by The National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) grants R21 NS116574, R01 NS100779, R01DK129691; Noah’s Hope/Hope 4 Bridget; The Lehrman Family Fund; the Department of Pediatrics at WashU Medicine; Irma and Norman Braman Endowment; Suzi and Scott Lustgarten Center Endowment; and the Children’s Hospital of Philadelphia Fronter Program Center for Precision Diagnosis and Therapy for Pediatric Motility Disorders.
Ziółkowska et al. Gene therapy prevents bowel dysmotility, enteric neuron degeneration and extends survival in lysosomal storage disorders. Science Translational Medicine. Jan. 15, 2025. DOI: 10.1126/scitranslmed.adj1445
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