Gene therapy for childhood Batten disease slows symptoms, extend lifespan
The study describes how Batten disease affects the function of half-billion nerve cells in the bowel wall that are part of the enteric nervous system. This new work shows enteric neurons in two mouse models of Batten disease degenerate in the bowel, paralleling neurodegeneration long known to occur in brain and spinal cord.
The 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 this 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, published in Science Translational Medicine, 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 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.”
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 researchers 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.
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 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 the 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,” the author 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.”
Another author 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 the author. “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.”
