Gene therapy improves bowel function in Batten mouse model
Therapy targeting nerve cells in gut also shown to increase survival rates
Gene therapy targeting nerve cells in the gut improved nerve cell survival and intestinal function — specifically that of the bowel — while also increasing survival rates in a mouse model of Batten disease, a new study by researchers at Washington University School of Medicine (WashU Medicine) in St. Louis shows.
The researchers and a parent advocate who lost two children to Batten say they hope this work will lead to new treatments for severe constipation and intestinal problems seen in youngsters with the rare disease.
“We are all miserable when we can’t poop. … It can be painful and a serious quality of life issue for the child and their families,” Jonathan Cooper, PhD, co-senior author of the study and a professor of pediatrics and genetics and neurology at WashU Medicine, said in a university news story.
Prior research had revealed a parallel pattern of neurodegeneration between nerve cells in the brain and those in the gastrointestinal tract in both mouse models of Batten and postmortem samples from children with the disease.
“We believe our studies in mice have demonstrated a novel and highly promising way to successfully treat [gastrointestinal] conditions with gene therapy,” Cooper said. “Importantly, we also established that the [gastrointestinal] issues were not secondary to the neurological changes in the brain or spinal cord caused by the disease, but happen in the bowel itself.”
The findings from this work were detailed in “Gene therapy ameliorates bowel dysmotility and enteric neuron degeneration and extends survival in lysosomal storage disorder mouse models.” The study was published in the journal Science Translational Medicine.
Parents of Batten children stressed to researcher impact of severe constipation
Batten disease refers to a group of neurological conditions caused by mutations in genes encoding for enzymes in the body that are involved in the breakdown of proteins that are no longer needed. As a result of these mutations, lipofuscins — partly broken down fats and proteins — accumulate to toxic levels inside lysosomes, the cellular compartments responsible for clearing waste products, leading to tissue and organ damage.
Nerve cells are particularly sensitive to this process and are progressively lost throughout the disease, resulting in symptoms like the gradual decline of motor and cognitive functions, vision problems, and seizures. However, children with Batten often have debilitating gastrointestinal symptoms, potentially associated with degenerating neurons in the enteric nervous system — a network of nerve cells within the gut wall responsible for regulating bowel function and gastrointestinal processes.
Cooper’s research was motivated by families affected by the disease, such as the VanHoutans, whose children Noah and Bridget were both diagnosed with Batten disease. The father, Tracy VanHoutan, became an advocate for rare disease research and founded the Noah’s Hope – Hope 4 Bridget Foundation, based in Illinois.
During patient advocacy meetings with Cooper and other researchers, families reported severe constipation as a daily issue for children living with Batten.
“Dr. Cooper is a special scientist because he seeks out patients and their families,” VanHoutan said. “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.”
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. … 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.
Robert O. Heuckeroth, MD, PhD, pediatric gastroenterologist at Children’s Hospital of Philadelphia and co-senior author of the study, joined with Cooper to investigate. Together, the scientists discovered that Batten disease also led to the degeneration of neurons in the gastrointestinal tract, causing problems with bowel function.
Their discoveries were made in mouse models of Batten disease and in the intestinal tissue of children who died from the disease.
“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 said. “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.”
Cooper’s previous research also demonstrated that supplying the missing enzyme, via enzyme replacement therapy, to the brain of animal models of Batten disease caused by mutations in the CLN1 or the CLN2 genes, slowed cellular degeneration.
New gene therapy found to improve bowel function in newborn mice
In this study, the team created a gene therapy that used a harmless virus to deliver a functional copy of the CLN1 or CLN2 gene to mice. This approach allowed the cells to produce the missing enzyme.
When the gene therapy was given to newborn mice, it prevented the loss of nerve cells in the animals’ enteric nervous system, and improved bowel function. Moreover, by preventing enteric neuronal degeneration the treatment extended the animals’ lifespan.
According to Heuckeroth, “the enteric nervous system controls most aspects of bowel function.”
“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,” Heuckeroth said.
Future research will focus on providing gene therapy to both the bowel and the brain, which the researchers believe will be necessary for optimal results. The scientists already are working to apply their findings to other Batten disease types, and to other neurodegenerative conditions affecting children.
“These data provide proof-of-principle evidence of [enteric nervous system] degeneration in … lysosomal storage diseases and suggest that gene therapy can ameliorate … disease, also improving survival,” the researchers wrote, noting that the therapy “still extended the lifespan of CLN1 disease mice” even in later stages of the disease.
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