Professor of pediatrics, genetics and 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 parents’ perspective led Cooper on a scientific quest that began four years ago (and continues today) to study the 500 million nerve cells in the intestinal wall that are part of the enteric nervous system and how Batten disease affects their function. . Their new work shows that enteric neurons in two mouse models of Batten disease degenerate in the intestine, paralleling neurodegeneration that has long been known to occur in the brain and spinal cord.
Cooper’s previous research also demonstrated that delivering the missing enzyme to the brain in mouse or sheep Batten disease models via enzyme replacement therapy slowed cellular degeneration. Now their latest study has discovered that gene therapy in mice produces the same protective effect in the intestine. This genetic treatment reduced intestinal symptoms and extended the lifespan of the mice by preventing degeneration of enteric neurons.
The findings, published January 15 in Scientific translational medicineIt could one day lead to new treatments for Batten disease, as well as other neurodegenerative disorders with gastrointestinal symptoms.
“We believe our studies in mice have demonstrated a novel and very promising way to successfully treat gastrointestinal conditions with gene therapy,” said Cooper, co-senior author of the study. “Importantly, we also established that the gastrointestinal problems were not secondary to neurological changes in the brain or spinal cord caused by the disease, but rather occur in the intestine itself.”
Patient-driven research
Batten disease refers to a group of inherited disorders of the nervous system 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 for the material built up inside 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 children with Batten disease is still unknown; However, some researchers have estimated that it affects about three in every 100,000 children in the US.
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 her home in Chicago to find scientists who could help her 5-year-old son, who had this extremely rare and understudied disease.
The two clicked immediately. They began to talk regularly. Together, they mourned Noah’s death 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 a prominent 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 for-profit business he founded after his son’s diagnosis. During one of those meetings, Cooper asked parents about everyday problems their children were experiencing.
Severe constipation, they told him. You might want to look into it, they suggested.
“And Dr. Cooper listened,” VanHoutan said. “Dr. Cooper is a special scientist because he seeks out patients and their families. No matter the age of the patient, he will get down to their level and ask and answer questions in a relatable way. He will talk to the parents, but also to the siblings and grandparents “He wants to know all the perspectives.”
Motivated by what he learned from families, Cooper turned his attention to the gut’s nervous system. Collaborating with Cooper is Robert O. Heuckeroth, MD, PhD, a pediatric gastroenterologist at Children’s Hospital of Philadelphia and professor of pediatrics and of cellular 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 gut.
Together, the scientists discovered that while Batten disease destroys nerve cells in the brain and spinal cord, it also kills neurons that are part of the enteric nervous system of the gastrointestinal tract.
His research on Batten disease in mouse models and in colon tissue from children who died from Batten disease demonstrated that the degeneration of nerve cells in the intestine occurs in parallel with events in the brain, following a pattern and a similar timeline. About half of the nerve cells normally present die in Batten mice as the disease progresses, causing problems with intestinal motility.
The basis for the treatment of these diseases is to introduce a functional copy of the defective gene. This is provided by a gene therapy virus that instructs cells to produce this missing enzyme and secretes it to treat nearby cells. Giving gene therapy to newborn mice with Batten disease prevented the loss of many nerve cells in the intestine and prevented problems related to intestinal function. Mice treated with gene therapy also lived significantly longer than untreated Batten disease mice.
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 gastrointestinal upset, cognitive and developmental impairment, skeletal and joint problems, vision problems, and physical deformities, among others.
“Our reasoning is that if nerve cells in the brain die because they are missing a key enzyme, then there is a high probability that nerve cells in other organ systems will also die,” Cooper explained. “And since a person has 500 million nerve cells in the intestine, about as many as in the spinal cord, it was important to determine whether this occurs, opening a completely new perspective on these diseases.”
Heuckeroth, a leading expert on the enteric nervous system whom Cooper affectionately calls his “co-pilot” in the research, added that damage to the enteric nervous system can profoundly affect intestinal function, causing debilitating symptoms such as vomiting, bloating, constipation and abdominal pain. . , malnutrition and predisposition to intestinal inflammation, sepsis and death.
“The enteric nervous system controls most aspects of intestinal function,” Heuckeroth said. “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 the gut, which they believe is necessary for optimal results.