AstroExo-HD · Astrocyte Exosome Cargo as a Mediator of Non-Cell-Autonomous Neurodegeneration in Huntington’s Disease

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Project objective

Huntington’s Disease (HD) is a fatal neurodegenerative disorder affecting 10-13/100,000 across Europe, with an annual economic burden of €3B+. No therapy halts or delays progression. Existing interventions such as antisense oligonucleotides are of limited efficacy, while current biomarkers (neurofilament light chain, mutant huntingtin in CSF, neuroimaging) either detect late-stage damage, lack cell-type specificity or require invasive sampling.This fellowship will investigate a novel mechanistic axis proposing that astrocytic proteostasis failure leads to altered extracellular vesicle (EV) signalling that contributes to neuronal dysfunction. The project leverages directly reprogrammed patient fibroblasts into astrocytes and neurons that retain transcriptomic and epigenetic signatures of aging, providing a uniquely relevant model of late-onset HD.The interdisciplinary approach integrates multi-omics profiling (proteomics, RNA-seq), bioinformatics-driven prioritisation, functional testing in patient-derived neurons and mechanistic validation of both toxic gain- and loss-of-function EV cargoes to define novel avenues for effective treatment identification. This design adds mechanistic depth often missing in current biomarker studies and ensures robustness across discovery, validation and translation.Expected outcomes include high-quality datasets, prioritized cargo candidates and functional assays adaptable to other neurodegenerative diseases (ALS, FTD, AD). These results will support the development of next-generation biomarkers (ADEVs measurable in biofluids) and lay the foundation for therapeutic strategies, such as nanobody-based neutralisation, while such development beyond the PF timeframe.Through targeted dissemination, IP protection, and intersectoral training this fellowship will strengthen EU’s role in precision neurodegeneration, while equipping me with advanced expertise, leadership skills, a broad professional network and a platform for independence.

Original text from CORDIS.

Participants

• SIEC BADAWCZA LUKASIEWICZ - PORT POLSKI OSRODEK ROZWOJU TECHNOLOGII · WrocawCoordinatorPoland

Links

• View on CORDIS
• DOI: 10.3030/101285604