Researchers have detailed the nerve cell degeneration that occurs in the intestinal nervous system due to Batten disease, a rare and deadly genetic disorder. In their latest findings, a team revealed that gene therapy administered to the intestines of mice with Batten disease symptoms successfully alleviated their conditions and increased their lifespan.
“The discomfort can be significant and affects the quality of life for both the child and their family,” stated a professor of pediatrics, genetics, and neurology at Washington University School of Medicine in St. Louis.
This parent insight initiated Cooper’s scientific journey four years ago, which remains ongoing, to investigate the approximately 500 million nerve cells located in the intestinal wall that form a part of the enteric nervous system, as well as how Batten disease impacts their functionality. His latest research demonstrates that enteric neurons in two mouse models of Batten disease deteriorate in the bowel, mirroring the degeneration seen in the brain and spinal cord.
Previous research by Cooper indicated that delivering the missing enzyme to the brain in models of Batten disease, whether in mice or sheep, via enzyme replacement therapy could slow cell degeneration. His most recent study found that gene therapy applied to the intestines of mice resulted in similar protective benefits. This genetic intervention mitigated bowel-related symptoms and prolonged the mice’s lives by preventing enteric neuron deterioration.
The results, which were published on January 15 in Science Translational Medicine, could eventually pave the way for innovative treatments for Batten disease and other neurodegenerative disorders that exhibit digestive symptoms.
“We believe our mouse studies have revealed a novel and very hopeful method to effectively address gastrointestinal conditions using gene therapy,” said Cooper, one of the study’s co-senior authors. “Importantly, we proved that gastrointestinal issues arose directly from the bowel and were not merely secondary effects of the neurological degeneration occurring in the brain or spinal cord.”
Research Driven by Patient Experiences
Batten disease encompasses a group of inherited nervous system disorders where children lack a vital enzyme that processes and recycles cellular waste. Also known as neuronal ceroid lipofuscinosis, the disease earns its name from the waste material that accumulates within cells. The absence of these enzymes leads to progressive brain injury and ultimately death. Cooper and his team are investigating the mechanisms behind this process.
The exact prevalence of Batten disease in children is uncertain; however, estimates suggest it impacts approximately three in every 100,000 children in the United States.
Tracy VanHoutan has two children affected by this disease. In 2009, he encountered Cooper at a rare disease conference in Hamburg, Germany, after his son, Noah, was diagnosed with a type of Batten disease. VanHoutan traveled over 4,000 miles from Chicago to connect with scientists who might assist his 5-year-old son as he battled this exceedingly rare and neglected disease.
The two formed an immediate bond and started regular conversations. Together, they grieved the loss of Noah in 2016, shortly before his 12th birthday, and again in December 2018 when VanHoutan’s daughter, Laine, succumbed to the disease at 12 years old.
As a strong advocate for rare disease research, VanHoutan invited Cooper to speak at patient-advocacy events, some held by Noah’s Hope-Hope4Bridget Foundation, a nonprofit he established after his son’s diagnosis. During these meetings, Cooper asked parents about their children’s daily struggles.
They recounted issues of severe constipation, suggesting he look into it.
“Dr. Cooper was attentive,” VanHoutan remarked. “He stands out because he actively seeks out patients and their families. Regardless of age, he engages with them at their level, asking and answering questions in a way they can understand. He converses with not only parents but also siblings and grandparents, wanting to capture all viewpoints.”
Inspired by what he learned from families, Cooper shifted his focus to the gut’s nervous system. He collaborates with Robert O. Heuckeroth, MD, PhD, a pediatric gastroenterologist at Children’s Hospital of Philadelphia, as well as a professor of pediatrics and cell and developmental biology at the University of Pennsylvania. Heuckeroth completed his graduate and medical education at WashU Medicine, where he developed an interest in the gut’s nervous system.
Together, the researchers found that while Batten disease seriously damages nerve cells in the brain and spinal cord, it similarly destroys neurons in the GI tract’s enteric nervous system.
Their studies involving Batten disease in mouse models and colon tissue from children who had died from the disorder showed that nerve cell degeneration in the gut aligns with similar changes in the brain, following an analogous process and timeline. Approximately half of the nerve cells usually found in Batten disease-affected mice perish as the disease advances, leading to bowel motility issues.
The primary treatment strategy involves introducing a correct version of the defective gene. This is delivered via a gene therapy virus that instructs cells to produce the missing enzyme, which helps to treat nearby cells. Administering gene therapy to newborn mice with Batten disease helped avert the loss of numerous nerve cells in the bowel and effectively addressed related bowel issues. Mice receiving gene therapy also lived significantly longer than those who did not receive treatment.
The team has commenced applying their discoveries to additional variants of Batten disease and related neurodegenerative conditions in children, such as mucopolysaccharidoses, another rare group of inherited disorders resulting from enzyme deficiencies that impact a cell’s capacity to break down materials. Their symptoms can include gastrointestinal distress, cognitive and developmental decline, and physical deformities, along with issues related to vision, joints, and skeletal structure.
“Our rationale is simple: if nerve cells in the brain die due to the absence of a crucial enzyme, there’s a strong likelihood that nerve cells in other organs can also perish,” Cooper elaborated. “With around half a billion nerve cells in the intestines—comparable to those in the spinal cord—recognizing this occurrence is vital, offering a new perspective on these conditions.”
Heuckeroth, a leading authority on the enteric nervous system, fondly referred to by Cooper as his “co-pilot” in research, noted that damage to this system can severely disrupt bowel functions, leading to debilitating symptoms like vomiting, bloating, constipation, abdominal pain, malnutrition, and increased risks of bowel inflammation, sepsis, and mortality.
“The enteric nervous system regulates most bowel functions,” Heuckeroth asserted. “We believe this research is the first to illustrate that a substantial disease affecting the enteric nervous system could be treated through gene therapy, at least in mouse models.”
Cooper and Heuckeroth indicated that future research will focus on applying simultaneous gene therapy targeted at both the brain and the bowel, which they believe will be crucial for achieving the best results.
