Abstract
Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia, marked by severe atrophy in the frontal and temporal cortex, leading to changes in personality, behavior, and language. Currently, there are no interventions to modify or prevent FTD progression. Loss-of-function mutations in the gene encoding progranulin are the second most common genetic cause of FTD. Ongoing clinical trials are focusing on elevating progranulin levels via antibody-therapeutics or adeno-associated viral gene transfer, which require repeated high systemic doses with minimal brain penetration or permanent genetic editing of endogenous cells, both of which can cause side effects. Given that microglia are the primary progranulin expressors in the brain, I propose exploring these cells as a therapeutic platform for FTD. I hypothesize that microglia can serve as living factories, continuously producing and locally releasing biologicals (e.g. progranulin) in the brain to modify FTD. This approach could circumvent the limitations of current therapeutic strategies. To achieve this, I will use an innovative xenotransplantation model, where human iPSC-derived microglia are transplanted into the mouse brain, followed by longitudinal behavioral, pathological and biomarker assessments, and single-nucleus RNA sequencing. If successful, my project could lay the groundwork for new treatments for other neurological diseases, including Alzheimer's disease and amyotrophic lateral sclerosis.
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