Batten disease hits the gut, but gene therapy may help

Batten disease, a group of genetic conditions affecting lysosomal function, leads to the accumulation of material inside cells and progressive neurodegeneration that is fatal. Children with Batten disease gradually lose motor and cognitive abilities and rarely survive into adulthood.

But kids with Batten disease also experience symptoms in organs outside the brain. After repeatedly hearing families of patients express concerns about bowel problems, Jonathan Cooper, an experimental translational neuroscientist at Washington University in St. Louis, decided to investigate further. In a recent study, he and his colleagues discovered significant gut neuron loss in two mouse models of Batten disease. They also found that delivering a gene therapy intravenously could partially prevent this loss while extending survival (1).

“We’ve published extensively on what happens in [these mice’s] brains and how to treat their brains and what goes on at a molecular level, the behavior, the pathology,” Cooper said, “but we knew nothing about their bowels.”

Cooper joined forces with Robert Heuckeroth, a pediatric gastroenterologist and researcher at the Children's Hospital of Philadelphia, to look at the guts of two mouse models of Batten disease, each representing the CLN1 and CLN2 disease forms, caused by mutations in distinct genes.

Their experiments revealed that by the disease’s end stage, both mouse models had lost around half of their myenteric neurons, which regulate bowel motility, along with changes in other bowel cell types like glia and macrophages. This cellular loss occurred in parallel with the neuronal loss occurring in the brain, beginning at roughly the same time. Colon tissue from an autopsy of a child who had died of CLN1 disease also showed significant neuronal and glial damage, suggesting that the disease likely impacts the bowel in humans as well.

We’ve published extensively on what happens in [these mice’s] brains and how to treat their brains and what goes on at a molecular level, the behavior, the pathology … but we knew nothing about their bowels.
- Jonathan Cooper, Washington University in St. Louis

The team then tested whether an adeno-associated virus-based gene therapy carrying the missing gene for each variant could prevent this neuronal loss. Previously, researchers had used gene therapy to treat the central nervous system of mouse and sheep models of variants of Batten disease by injecting it directly into the animals’ cerebral ventricles or brain parenchyma (2,3). This time, however, they administered it intravenously to newborn mice. By delivering it early in life, they hoped that the gene therapy could distribute throughout the body and start expressing the gene product in some cells, including in the myenteric neurons. The treatment significantly reduced neuron loss in the bowel and extended the lifespan of CLN1 mice by about 70 percent and CLN2 mice by nearly 30 percent, compared to untreated mice.

The treatment was less effective in three-week-old postweaning mice, with lifespan extension much more limited in CLN1 mice and absent in CLN2 mice. One factor that may partly explain the difference in efficacy is that in newborns, gene therapy may reach the central nervous system more easily because the blood-brain barrier has not fully formed yet. However, Cooper emphasized that even if the intravenous treatment only partly reached the brain, its effect was nowhere near as much as injecting it directly into the cerebrospinal fluid. Moreover, the blood-brain barrier forms early in human embryos, making it unrealistic to treat the brain via the blood.

“We’re probably going to have to treat both the brain and the rest of the body by two separate routes,” said Cooper. The team is securing funding to test whether treating both the brain directly and the body systemically have better overall efficacy in mice than just treating the brain alone.

Neuroscientist Samantha Murray from Lincoln University, who was not involved in the study, said its results highlight the need for scientists to consider pathology outside the central nervous system when treating these diseases.

Murray further noted that “[gastrointestinal] symptoms can be really debilitating for children with Batten disease and difficult for the caregivers to manage.” Thus, even if it’s unclear whether combining a central nervous system-directed treatment with a systemic therapy would further extend survival, she said that such an approach is likely to improve the quality of life of these children.

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