Federal Project Grant Award Summary

The National Institute on Aging awarded UCSF a $680,792 Project Grant under the Aging Research program (CFDA 93.866) effective February 1, 2026, with a completion date of December 31, 2030. This award funds research to develop and optimize CRISPR/Cas9 genome editing strategies targeting MAPT gene mutations associated with frontotemporal dementia (FTD). The research deliverables include: (1) optimization of a dual single-guide RNA (sgRNA) strategy to excise mutant MAPT alleles in patient-derived induced pluripotent stem cells and neurons while preserving non-diseased allele expression; (2) in vivo validation using FTD mouse models with adeno-associated virus delivery to determine therapeutic efficacy and optimal dosing; and (3) characterization of three genes embedded in the MAPT locus to identify additional therapeutic targets and inform broader therapeutic approaches for tau-related pathology.

The research will produce a candidate gene-editing strategy optimized for human neurons in vitro with defined therapeutic parameters suitable for clinical translation when paired with human-specific delivery systems. This work addresses an urgent clinical need, as FTD represents 10-20% of dementia cases with no effective treatments, and approximately 9% of FTD cases result from MAPT mutations. Deliverables will include technical validation data, animal model efficacy studies, and mechanistic insights into MAPT locus function that advance understanding of tau-mediated neurodegeneration and provide a foundation for future clinical development.