Fatal neurodegenerative disease in kids also affects the bowel—gene therapy may help microbiologystudy

Researchers at Washington University School of Medicine in St. Louis have described the neurodegeneration that occurs in the nervous system of the bowel in Batten disease, a rare and fatal genetic condition. In their latest study, a team led by Jonathan Cooper, Ph.D., professor of pediatrics at WashU Medicine, has shown that gene therapy to the bowel in mice modeling Batten disease reduced symptoms and extended lifespan.

The study is published in the journal Science Translational Medicine.

As a leading researcher of rare diseases that affect children’s brains, Jonathan D. Cooper, Ph.D., thought little about the gastrointestinal (GI) system. That is, until the parents of children with a condition that Cooper studies urged him to investigate why debilitating digestive issues troubled their kids, who suffer from an incurable and fatal neurodegenerative brain condition called Batten disease.

Doctors had informed the parents that their children could succumb to blindness, seizures, dementia, an inability to walk, and would die in childhood. But the parents told Cooper they felt unprepared for the severe constipation and intestinal problems their kids also experienced.

“We are all miserable when we can’t poop,” said Cooper, a professor of pediatrics, of genetics and of neurology at Washington University School of Medicine in St. Louis. “It can be painful and a serious quality of life issue for the child and their families.”

The parent perspective led Cooper on a scientific quest that began four years ago—and continues today—to study the half-billion nerve cells in the bowel wall that are part of the enteric nervous system and how Batten disease affects their function. His new work shows enteric neurons in two mouse models of Batten disease degenerate in the bowel, paralleling neurodegeneration long known to occur in the brain and spinal cord.

Cooper’s prior research also showed that supplying the missing enzyme to the brain in mouse or sheep Batten disease models via enzyme replacement therapy slowed cellular degeneration. Now his latest study has found that gene therapy in mice produced the same protective effect in the bowel. This genetic treatment reduced bowel symptoms and extended the lifespan of the mice by preventing enteric neuron degeneration.

The findings may one day lead to new treatments for Batten disease as well as for other neurodegenerative disorders with gastrointestinal symptoms.

“We believe our studies in mice have demonstrated 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 happened in the bowel itself.”

Patient-driven research

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. Cooper and his colleagues are exploring exactly how this happens.

The exact number of kids with Batten disease remains unknown; however, some researchers have estimated it affects around three out of every 100,000 children in the U.S.

Two of Tracy VanHoutan’s children had the disease. The father met Cooper in 2009 at a rare disease conference in Hamburg, Germany, after his son, Noah, was diagnosed with a form of Batten disease. VanHoutan had traveled more than 4,000 miles from his home in Chicago to find scientists who might help his 5-year-old-boy, suffering from this extremely rare and understudied disease.

The two clicked immediately. They began speaking regularly. Together, they grieved when Noah died in 2016, just before his 12th birthday, and again, less than two years later, in December 2018, when VanHoutan’s daughter, Laine, died from the disease at age 12.

VanHoutan, who has become an accomplished advocate for rare disease research, invited Cooper to speak at patient-advocacy meetings, some of which were organized through Noah’s Hope-Hope4Bridget Foundation, the nonprofit he founded after his son’s diagnosis. During one of those meetings, Cooper asked parents about the day-to-day issues their children experienced.

Severe constipation, they told him. You might want to investigate it, they suggested.

“And Dr. Cooper listened,” VanHoutan said. “Dr. Cooper is a special scientist because he seeks out patients and their families. It doesn’t matter how old the patient is, he will get on their level and ask and answer questions in a relatable manner. He’ll talk to the parents but also the siblings and grandparents. He wants to know all perspectives.”

Motivated by what he learned from the families, Cooper turned his attention to the nervous system in the gut. Collaborating with Cooper is Robert O. Heuckeroth, MD, Ph.D., a pediatric gastroenterologist at Children’s Hospital of Philadelphia and a professor of pediatrics and of cell and developmental biology at the University of Pennsylvania. Heuckeroth completed his graduate and medical training at WashU Medicine where he first became interested in the nervous system of the bowel.

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 mouse models and in colon tissue 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. About half of the nerve cells normally present die in Batten mice as the disease progresses, causing problems with bowel motility.

The basis for treating these diseases is to introduce a working copy of the defective gene. This is supplied by a gene therapy virus that instructs cells to make this missing enzyme, secreting it to treat nearby cells. Giving gene therapy to newborn mice with Batten disease prevented the loss of many nerve cells in the bowel and prevented related problems with bowel function. The mice treated by gene therapy also lived significantly longer than untreated Batten disease mice.

The researchers have begun to apply their findings to other forms of Batten disease and similar neurodegenerative conditions in children, such as mucopolysaccharidoses, another group of rare inherited diseases caused by enzyme deficiencies that thwart a cell’s ability to break down material. Symptoms include GI distress, cognitive and developmental decline, skeletal and joint issues, vision impairment and physical deformities, among others.

“Our reasoning is that if nerve cells in the brain die because they’re missing a key enzyme, then there’s a high probability nerve cells in other organ systems could also die,” Cooper explained. “And given that a person has half a billion nerve cells in their bowels, about as many as in the spinal cord, it was important to determine if this occurs, opening up a whole new perspective on these diseases.”

Heuckeroth, a leading expert in the enteric nervous system whom Cooper fondly calls his “co-pilot” in research, added that damage to the enteric nervous system can profoundly impair bowel function, causing debilitating symptoms such as vomiting, distension, constipation, abdominal pain, malnutrition and a predisposition to bowel inflammation, sepsis and death.

“The enteric nervous system controls most aspects of bowel function,” said Heuckeroth. “We believe this work shows for the first time that a serious disease of the enteric nervous system can be treated by gene therapy, at least in mice.”

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.