A child’s own immune system may be attacking the brain’s protective outer lining, accelerating the neurological damage seen in rare genetic diseases called lysosomal storage disorders (LSDs). These childhood conditions, often compared to paediatric Alzheimer’s, currently have almost no treatments. The brain’s borders—the meninges—are hubs of immune activity, and recent evidence suggests that immune dysfunction there can worsen neurodegeneration. This project will test whether targeting inflammation in the meninges can slow brain damage in LSD models, and whether anti-inflammatory molecules can protect neurons. It will also analyse biomarkers from a small group of children already enrolled in an early-stage clinical trial. If successful, the work could reveal new treatment targets not only for LSDs but for broader neurodegenerative diseases where immune-driven damage plays a role. The findings may also provide practical biomarkers to track disease progression and measure whether experimental therapies are working—tools that are currently missing for these devastating conditions.
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Lysosomal storage disorders (LSDs) are a group of rare genetic diseases affecting children, for whom there are almost no treatment options. Genetic mutations cause problems in the lysosomes of cells, leading to neurological problems, cognitive decline and ultimately death. Some of these processes are similar to those found in Alzheimer’s Disease (AD) and children are often referred to as having paediatric AD. Therefore, understanding the processes in these diseases will have broad implications for neurodegenerative research. This project aims to address if the immune system may play a fundamental role in exacerbating neurodegeneration in LSDs. A major advance of the past decade is the understanding that immune system plays a fundamental role in brain function in health and disease. At the cutting-edge of this research is understanding how the brain's borders, which are hubs of immune activity, drive brain disease. The specific aims of this research are to: 1) Experimentally target the brain's borders, called the meninges, to improve brain function in a model of LSDs. 2) Test whether novel anti-inflammatory molecules can protect from ongoing brain damage in models of LSDs. 3) Investigate biomarkers of CNS disease progression and treatment efficacy in a rare cohort of patients participating in an open label Phase I-II clinical trial. The potential applications and benefits are both specific and broad. This research programme has the potential to reveal new targetable pathways, understand underlying neurodegenerative mechanisms (not limited to LSDs), provide novel biomarkers to assess treatment efficacy and, crucially, enable experimental treatments in patients either in future or current clinical trials.
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